@article{pmid37156755,
title = {Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study},
author = {A Inkeri Lokki and Zhen Ren and Michael Triebwasser and Emma Daly and  and Markus Perola and Kirsi Auro and Richard Burwick and Jane E Salmon and Mark Daly and Hannele Laivuori and John P Atkinson and Anuja Java and Seppo Meri},
doi = {10.1111/1471-0528.17529},
issn = {1471-0528},
year  = {2023},
date = {2023-11-01},
journal = {BJOG},
volume = {130},
number = {12},
pages = {1473--1482},
abstract = {OBJECTIVE: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia.nnDESIGN: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls.nnSETTING: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven.nnPOPULATION: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts.nnMETHODS: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type.nnMAIN OUTCOME MEASURES: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations.nnRESULTS: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V.nnCONCLUSIONS: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37593040,
title = { regulates early developmental sleep in },
author = {Jaclyn Durkin and Amy R Poe and Samuel J Belfer and Anyara Rodriguez and Si Hao Tang and James A Walker and Matthew S Kayser},
doi = {10.1016/j.nbscr.2023.100101},
issn = {2451-9944},
year  = {2023},
date = {2023-11-01},
journal = {Neurobiol Sleep Circadian Rhythms},
volume = {15},
pages = {100101},
abstract = {Sleep disturbances are common in neurodevelopmental disorders, but knowledge of molecular factors that govern sleep in young animals is lacking. Evidence across species, including , suggests that juvenile sleep has distinct functions and regulatory mechanisms in comparison to sleep in maturity. In flies, manipulation of most known adult sleep regulatory genes is not associated with sleep phenotypes during early developmental (larval) stages. Here, we examine the role of the neurodevelopmental disorder-associated gene  () in sleep during numerous developmental periods. Mutations in  () are associated with sleep and circadian disorders in humans and adult flies. We find in flies that  acts to regulate sleep across the lifespan, beginning during larval stages.  is required in neurons for this function, as is signaling via the Alk pathway. These findings identify  as one of a small number of genes positioned to regulate sleep across developmental periods.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37005744,
title = {Unraveling non-participation in genomic research: A complex interplay of barriers, facilitators, and sociocultural factors},
author = {Allyn McConkie-Rosell and Rebecca C Spillmann and Kelly Schoch and Jennifer A Sullivan and Nicole Walley and Marie McDonald and  and Stephen R Hooper and Vandana Shashi},
doi = {10.1002/jgc4.1707},
issn = {1573-3599},
year  = {2023},
date = {2023-10-01},
journal = {J Genet Couns},
volume = {32},
number = {5},
pages = {993--1008},
abstract = {Although genomic research offering next-generation sequencing (NGS) has increased the diagnoses of rare/ultra-rare disorders, populations experiencing health disparities infrequently participate in these studies. The factors underlying non-participation would most reliably be ascertained from individuals who have had the opportunity to participate, but decline. We thus enrolled parents of children and adult probands with undiagnosed disorders who had declined genomic research offering NGS with return of results with undiagnosed disorders (Decliners, n = 21) and compared their data to those who participated (Participants, n = 31). We assessed: (1) practical barriers and facilitators, (2) sociocultural factors-genomic knowledge and distrust, and (3) the value placed upon a diagnosis by those who declined participation. The primary findings were that residence in rural and medically underserved areas (MUA) and higher number of barriers were significantly associated with declining participation in the study. Exploratory analyses revealed multiple co-occurring practical barriers, greater emotional exhaustion and research hesitancy in the parents in the Decliner group compared to the Participants, with both groups identifying a similar number of facilitators. The parents in the Decliner group also had lower genomic knowledge, but distrust of clinical research was not different between the groups. Importantly, despite their non-participation, those in the Decliner group indicated an interest in obtaining a diagnosis and expressed confidence in being able to emotionally manage the ensuing results. Study findings support the concept that some families who decline participation in diagnostic genomic research may be experiencing pile-up with exhaustion of family resources - making participation in the genomic research difficult. This study highlights the complexity of the factors that underlie non-participation in clinically relevant NGS research. Thus, approaches to mitigating barriers to NGS research participation by populations experiencing health disparities need to be multi-pronged and tailored so that they can benefit from state-of -the art genomic technologies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37794142,
title = {The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion},
author = {Rinki Murphy and Kevin Colclough and Toni I Pollin and Jennifer M Ikle and Pernille Svalastoga and Kristin A Maloney and Cécile Saint-Martin and Janne Molnes and  and Shivani Misra and Ingvild Aukrust and Elisa de Franco and Sarah E Flanagan and Pål R Njølstad and Liana K Billings and Katharine R Owen and Anna L Gloyn},
doi = {10.1038/s43856-023-00369-8},
issn = {2730-664X},
year  = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {136},
abstract = {BACKGROUND: Monogenic diabetes presents opportunities for precision medicine but is underdiagnosed. This review systematically assessed the evidence for (1) clinical criteria and (2) methods for genetic testing for monogenic diabetes, summarized resources for (3) considering a gene or (4) variant as causal for monogenic diabetes, provided expert recommendations for (5) reporting of results; and reviewed (6) next steps after monogenic diabetes diagnosis and (7) challenges in precision medicine field.nnMETHODS: Pubmed and Embase databases were searched (1990-2022) using inclusion/exclusion criteria for studies that sequenced one or more monogenic diabetes genes in at least 100 probands (Question 1), evaluated a non-obsolete genetic testing method to diagnose monogenic diabetes (Question 2). The risk of bias was assessed using the revised QUADAS-2 tool. Existing guidelines were summarized for questions 3-5, and review of studies for questions 6-7, supplemented by expert recommendations. Results were summarized in tables and informed recommendations for clinical practice.nnRESULTS: There are 100, 32, 36, and 14 studies included for questions 1, 2, 6, and 7 respectively. On this basis, four recommendations for who to test and five on how to test for monogenic diabetes are provided. Existing guidelines for variant curation and gene-disease validity curation are summarized. Reporting by gene names is recommended as an alternative to the term MODY. Key steps after making a genetic diagnosis and major gaps in our current knowledge are highlighted.nnCONCLUSIONS: We provide a synthesis of current evidence and expert opinion on how to use precision diagnostics to identify individuals with monogenic diabetes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37453564,
title = {Genome-Wide Association Study Identifies 4 Novel Risk Loci for Small Intestinal Neuroendocrine Tumors Including a Missense Mutation in LGR5},
author = {Anil K Giri and Mervi Aavikko and Linnea Wartiovaara and Toni Lemmetyinen and Juha Karjalainen and Juha Mehtonen and Kimmo Palin and Niko Välimäki and Max Tamlander and Riikka Saikkonen and Auli Karhu and Ekaterina Morgunova and Benjamin Sun and Heiko Runz and Priit Palta and Shuang Luo and Heikki Joensuu and Tomi P Mäkelä and Iiro Kostiainen and Camilla Schalin-Jäntti and FinnGen and Aarno Palotie and Lauri A Aaltonen and Saara Ollila and Mark J Daly},
doi = {10.1053/j.gastro.2023.06.031},
issn = {1528-0012},
year  = {2023},
date = {2023-10-01},
journal = {Gastroenterology},
volume = {165},
number = {4},
pages = {861--873},
abstract = {BACKGROUND & AIMS: Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported.nnMETHODS: Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls).nnRESULTS: We identified 6 genome-wide significant (P < 5 × 10) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10) was a missense variant (p.Cys712Phe) in the LGR5 gene, a bona-fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 patients with SI-NETs, as well as in the UK Biobank exome sequence data (n = 92 cases and n = 392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling.nnCONCLUSIONS: Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37794113,
title = {Utility and precision evidence of technology in the treatment of type 1 diabetes: a systematic review},
author = {Laura M Jacobsen and Jennifer L Sherr and Elizabeth Considine and Angela Chen and Sarah M Peeling and Margo Hulsmans and Sara Charleer and Marzhan Urazbayeva and Mustafa Tosur and Selma Alamarie and Maria J Redondo and Korey K Hood and Peter A Gottlieb and Pieter Gillard and Jessie J Wong and Irl B Hirsch and Richard E Pratley and Lori M Laffel and Chantal Mathieu and },
doi = {10.1038/s43856-023-00358-x},
issn = {2730-664X},
year  = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {132},
abstract = {BACKGROUND: The greatest change in the treatment of people living with type 1 diabetes in the last decade has been the explosion of technology assisting in all aspects of diabetes therapy, from glucose monitoring to insulin delivery and decision making. As such, the aim of our systematic review was to assess the utility of these technologies as well as identify any precision medicine-directed findings to personalize care.nnMETHODS: Screening of 835 peer-reviewed articles was followed by systematic review of 70 of them (focusing on randomized trials and extension studies with ≥50 participants from the past 10 years).nnRESULTS: We find that novel technologies, ranging from continuous glucose monitoring systems, insulin pumps and decision support tools to the most advanced hybrid closed loop systems, improve important measures like HbA1c, time in range, and glycemic variability, while reducing hypoglycemia risk. Several studies included person-reported outcomes, allowing assessment of the burden or benefit of the technology in the lives of those with type 1 diabetes, demonstrating positive results or, at a minimum, no increase in self-care burden compared with standard care. Important limitations of the trials to date are their small size, the scarcity of pre-planned or powered analyses in sub-populations such as children, racial/ethnic minorities, people with advanced complications, and variations in baseline glycemic levels. In addition, confounders including education with device initiation, concomitant behavioral modifications, and frequent contact with the healthcare team are rarely described in enough detail to assess their impact.nnCONCLUSIONS: Our review highlights the potential of technology in the treatment of people living with type 1 diabetes and provides suggestions for optimization of outcomes and areas of further study for precision medicine-directed technology use in type 1 diabetes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37794082,
title = {Genotype-stratified treatment for monogenic insulin resistance: a systematic review},
author = {Robert K Semple and Kashyap A Patel and Sungyoung Auh and  and Rebecca J Brown},
doi = {10.1038/s43856-023-00368-9},
issn = {2730-664X},
year  = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {134},
abstract = {BACKGROUND: Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology.nnMETHODS: Systematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy.nnRESULTS: 10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions.nnCONCLUSIONS: The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37271495,
title = {Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care},
author = {Meghan C Halley and Jennifer L Young and Charis Tang and Kevin T Mintz and Sawyer Lucas-Griffin and AudreyStephannie Maghiro and Euan A Ashley and Holly K Tabor and },
doi = {10.1016/j.jpeds.2023.113537},
issn = {1097-6833},
year  = {2023},
date = {2023-10-01},
journal = {J Pediatr},
volume = {261},
pages = {113537},
abstract = {OBJECTIVE: To explore the perspectives of parents of undiagnosed children enrolled in genomic diagnosis research regarding their motivations for enrolling their children, their understanding of the potential burdens and benefits, and the extent to which their experiences ultimately aligned with or diverged from their original expectations.nnSTUDY DESIGN: In-depth interviews were conducted with parents, audio-recorded and transcribed. A structured codebook was applied to each transcript, after which iterative memoing was used to identify themes.nnRESULTS: Fifty-four parents participated, including 17 (31.5%) whose child received a diagnosis through research. Themes describing parents' expectations and experiences of genomic diagnosis research included (1) the extent to which parents' motivations for participation focused on their hope that it would directly benefit their child, (2) the ways in which parents' frustrations regarding the research process confused the dual clinical and research goals of their participation, and (3) the limited clinical benefits parents ultimately experienced for their children.nnCONCLUSIONS: Our results suggest that parents of undiagnosed children seeking enrollment in genomic diagnosis research are at risk of a form of therapeutic misconception-in this case, diagnostic misconception. These findings indicate the need to examine the processes and procedures associated with this research to communicate appropriately and balance the potential burdens and benefits of study participation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37632486,
title = {An Environmental Scan of Consumer-Initiated Germline Genetic Testing for Health Risks},
author = {Hannah G Kirby and Heidi L Rehm and Leland E Hull},
doi = {10.1016/j.mayocp.2023.04.008},
issn = {1942-5546},
year  = {2023},
date = {2023-10-01},
journal = {Mayo Clin Proc},
volume = {98},
number = {10},
pages = {1529--1543},
abstract = {As patient access to laboratory testing outside the clinic grows, health care providers can expect to confront increasing questions about the utility and interpretation of consumer-initiated genetic testing for health risks. We sought to characterize the marketplace diversity of consumer-initiated germline genetic testing options. An environmental scan was conducted to identify germline genetic testing companies that offer testing for at least one diagnosable health condition and are available for purchase by consumers in the US market without a visit to one's health care provider. We limited our scope to tests available between October 1, 2019, and September 30, 2021. We characterized variability in the content and processes used by 21 companies offering 74 distinct test products that met our inclusion and exclusion criteria. A minority (8 of 21 companies) offered tests that assessed the presence of at least 1 US Centers for Disease Control and Prevention Tier 1 condition for which detection can impact an individual's clinical care and for which evidence-based guidelines for detection and management exist.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37794196,
title = {Precision gestational diabetes treatment: a systematic review and meta-analyses},
author = {Jamie L Benham and Véronique Gingras and Niamh-Maire McLennan and Jasper Most and Jennifer M Yamamoto and Catherine E Aiken and Susan E Ozanne and Rebecca M Reynolds and },
doi = {10.1038/s43856-023-00371-0},
issn = {2730-664X},
year  = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {135},
abstract = {BACKGROUND: Gestational Diabetes Mellitus (GDM) affects approximately 1 in 7 pregnancies globally. It is associated with short- and long-term risks for both mother and baby. Therefore, optimizing treatment to effectively treat the condition has wide-ranging beneficial effects. However, despite the known heterogeneity in GDM, treatment guidelines and approaches are generally standardized. We hypothesized that a precision medicine approach could be a tool for risk-stratification of women to streamline successful GDM management. With the relatively short timeframe available to treat GDM, commencing effective therapy earlier, with more rapid normalization of hyperglycaemia, could have benefits for both mother and fetus.nnMETHODS: We conducted two systematic reviews, to identify precision markers that may predict effective lifestyle and pharmacological interventions.nnRESULTS: There was a paucity of studies examining precision lifestyle-based interventions for GDM highlighting the pressing need for further research in this area. We found a number of precision markers identified from routine clinical measures that may enable earlier identification of those requiring escalation of pharmacological therapy (to metformin, sulphonylureas or insulin). This included previous history of GDM, Body Mass Index and blood glucose concentrations at diagnosis.nnCONCLUSIONS: Clinical measurements at diagnosis could potentially be used as precision markers in the treatment of GDM. Whether there are other sensitive markers that could be identified using more complex individual-level data, such as omics, and if these can feasibly be implemented in clinical practice remains unknown. These will be important to consider in future studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37708901,
title = {Current insights and emerging trends in early-onset type 2 diabetes},
author = {Shivani Misra and Calvin Ke and Shylaja Srinivasan and Alpesh Goyal and Moffat J Nyriyenda and Jose C Florez and Kamlesh Khunti and Dianna J Magliano and Andrea Luk},
doi = {10.1016/S2213-8587(23)00225-5},
issn = {2213-8595},
year  = {2023},
date = {2023-10-01},
journal = {Lancet Diabetes Endocrinol},
volume = {11},
number = {10},
pages = {768--782},
abstract = {Type 2 diabetes diagnosed in childhood or early adulthood is termed early-onset type 2 diabetes. Cases of early-onset type 2 diabetes are increasing rapidly globally, alongside rising obesity. Compared with a diagnosis later in life, an earlier-onset diagnosis carries an unexplained excess risk of microvascular complications, adverse cardiovascular outcomes, and earlier death. Women with early-onset type 2 diabetes also have a higher risk of adverse pregnancy outcomes. The high burden of complications renders individuals with early-onset type 2 diabetes at future risk of multimorbidity and interventions to reverse these concerning trends should be a priority. Within the early-onset cohort, disease pathophysiology and interventions have been better studied in paediatric-onset (<19 years) type 2 diabetes compared to adults; however, young adults aged 19-39 years (a larger number proportionally) are not well characterised and are also invisible in the current evidence base supporting management, which is derived from trials in later-onset type 2 diabetes. Young adults with type 2 diabetes face challenges in self-management that older individuals are less likely to experience (being in education or of working age, higher diabetes distress, and possible obesity-related stigma and diabetes-related stigma). There is a major research gap as to the optimal strategies to deploy in managing type 2 diabetes in adolescents and young adults, given that current models of care appear to not work as well in this age group. In the face of manifold risk factors (obesity, female sex, social deprivation, non-White European ethnicity, and genetic risk factors) prevention strategies with tailored lifestyle interventions, where needed, are likely to have greater success, but more evidence is needed. In this Review, we draw on evidence from both adolescents and young adults to provide a contemporary update on the current insights and emerging trends in early-onset type 2 diabetes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37794046,
title = {PAM-flexible genome editing with an engineered chimeric Cas9},
author = {Lin Zhao and Sabrina R T Koseki and Rachel A Silverstein and Nadia Amrani and Christina Peng and Christian Kramme and Natasha Savic and Martin Pacesa and Tomás C Rodríguez and Teodora Stan and Emma Tysinger and Lauren Hong and Vivian Yudistyra and Manvitha R Ponnapati and Joseph M Jacobson and George M Church and Noah Jakimo and Ray Truant and Martin Jinek and Benjamin P Kleinstiver and Erik J Sontheimer and Pranam Chatterjee},
doi = {10.1038/s41467-023-41829-y},
issn = {2041-1723},
year  = {2023},
date = {2023-10-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {6175},
abstract = {CRISPR enzymes require a defined protospacer adjacent motif (PAM) flanking a guide RNA-programmed target site, limiting their sequence accessibility for robust genome editing applications. In this study, we recombine the PAM-interacting domain of SpRY, a broad-targeting Cas9 possessing an NRN > NYN (R = A or G, Y = C or T) PAM preference, with the N-terminus of Sc + +, a Cas9 with simultaneously broad, efficient, and accurate NNG editing capabilities, to generate a chimeric enzyme with highly flexible PAM preference: SpRYc. We demonstrate that SpRYc leverages properties of both enzymes to specifically edit diverse PAMs and disease-related loci for potential therapeutic applications. In total, the approaches to generate SpRYc, coupled with its robust flexibility, highlight the power of integrative protein design for Cas9 engineering and motivate downstream editing applications that require precise genomic positioning.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37315746,
title = {Immunomodulation of the donor lung with CRISPR-mediated activation of IL-10 expression},
author = {Kumi Mesaki and Stephen Juvet and Jonathan Yeung and Zehong Guan and Gavin W Wilson and Jim Hu and Alan R Davidson and Benjamin P Kleinstiver and Marcelo Cypel and Mingyao Liu and Shaf Keshavjee},
doi = {10.1016/j.healun.2023.06.001},
issn = {1557-3117},
year  = {2023},
date = {2023-10-01},
journal = {J Heart Lung Transplant},
volume = {42},
number = {10},
pages = {1363--1377},
abstract = {BACKGROUND: Inflammatory injury in the donor lung remains a persistent challenge in lung transplantation that limits donor organ usage and post-transplant outcomes. Inducing immunomodulatory capacity in donor organs could address this unsolved clinical problem. We sought to apply clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) technologies to the donor lung to fine-tune immunomodulatory gene expression, exploring for the first time the therapeutic use of CRISPR-mediated transcriptional activation in the whole donor lung.nnMETHODS: We explored the feasibility of CRISPR-mediated transcriptional upregulation of interleukin 10 (IL-10), a key immunomodulatory cytokine, in vitro and in vivo. We first evaluated the potency, titratability, and multiplexibility of the gene activation in rat and human cell lines. Next, in vivo CRISPR-mediated IL-10 activation was characterized in rat lungs. Finally, the IL-10-activated donor lungs were transplanted into recipient rats to assess the feasibility in a transplant setting.nnRESULTS: The targeted transcriptional activation induced robust and titrable IL-10 upregulation in vitro. The combination of guide RNAs also facilitated multiplex gene modulation, that is, simultaneous activation of IL-10 and IL1 receptor antagonist. In vivo profiling demonstrated that adenoviral delivery of Cas9-based activators to the lung was feasible with the use of immunosuppression, which is routinely applied to organ transplant recipients. The transcriptionally modulated donor lungs retained IL-10 upregulation in isogeneic and allogeneic recipients.nnCONCLUSIONS: Our findings highlight the potential of CRISPR epigenome editing to improve lung transplant outcomes by creating a more favorable immunomodulatory environment in the donor organ, a paradigm that may be extendable to other organ transplants.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37766997,
title = {Bayesian multivariate genetic analysis improves translational insights},
author = {Sarah M Urbut and Satoshi Koyama and Whitney Hornsby and Rohan Bhukar and Sumeet Kheterpal and Buu Truong and Margaret S Selvaraj and Benjamin Neale and Christopher J O'Donnell and Gina M Peloso and Pradeep Natarajan},
doi = {10.1016/j.isci.2023.107854},
issn = {2589-0042},
year  = {2023},
date = {2023-10-01},
journal = {iScience},
volume = {26},
number = {10},
pages = {107854},
abstract = {While lipid traits are known essential mediators of cardiovascular disease, few approaches have taken advantage of their shared genetic effects. We apply a Bayesian multivariate size estimator, mash, to GWAS of four lipid traits in the Million Veterans Program (MVP) and provide posterior mean and local false sign rates for all effects. These estimates borrow information across traits to improve effect size accuracy. We show that controlling local false sign rates accurately and powerfully identifies replicable genetic associations and that multivariate control furthers the ability to explain complex diseases. Our application yields high concordance between independent datasets, more accurately prioritizes causal genes, and significantly improves polygenic prediction beyond state-of-the-art methods by up to 59% for lipid traits. The use of Bayesian multivariate genetic shrinkage has yet to be applied to human quantitative trait GWAS results, and we present a staged approach to prediction on a polygenic scale.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37794119,
title = {Participant characteristics in the prevention of gestational diabetes as evidence for precision medicine: a systematic review and meta-analysis},
author = {Siew Lim and Wubet Worku Takele and Kimberly K Vesco and Leanne M Redman and Wesley Hannah and Maxine P Bonham and Mingling Chen and Sian C Chivers and Andrea J Fawcett and Jessica A Grieger and Nahal Habibi and Gloria K W Leung and Kai Liu and Eskedar Getie Mekonnen and Maleesa Pathirana and Alejandra Quinteros and Rachael Taylor and Gebresilasea G Ukke and Shao J Zhou and  and Jami Josefson},
doi = {10.1038/s43856-023-00366-x},
issn = {2730-664X},
year  = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {137},
abstract = {BACKGROUND: Precision prevention involves using the unique characteristics of a particular group to determine their responses to preventive interventions. This study aimed to systematically evaluate the participant characteristics associated with responses to interventions in gestational diabetes mellitus (GDM) prevention.nnMETHODS: We searched MEDLINE, EMBASE, and Pubmed to identify lifestyle (diet, physical activity, or both), metformin, myoinositol/inositol and probiotics interventions of GDM prevention published up to May 24, 2022.nnRESULTS: From 10347 studies, 116 studies (n = 40940 women) are included. Physical activity results in greater GDM reduction in participants with a normal body mass index (BMI) at baseline compared to obese BMI (risk ratio, 95% confidence interval: 0.06 [0.03, 0.14] vs 0.68 [0.26, 1.60]). Combined diet and physical activity interventions result in greater GDM reduction in participants without polycystic ovary syndrome (PCOS) than those with PCOS (0.62 [0.47, 0.82] vs 1.12 [0.78-1.61]) and in those without a history of GDM than those with unspecified GDM history (0.62 [0.47, 0.81] vs 0.85 [0.76, 0.95]). Metformin interventions are more effective in participants with PCOS than those with unspecified status (0.38 [0.19, 0.74] vs 0.59 [0.25, 1.43]), or when commenced preconception than during pregnancy (0.21 [0.11, 0.40] vs 1.15 [0.86-1.55]). Parity, history of having a large-for-gestational-age infant or family history of diabetes have no effect on intervention responses.nnCONCLUSIONS: GDM prevention through metformin or lifestyle differs according to some individual characteristics. Future research should include trials commencing preconception and provide results disaggregated by a priori defined participant characteristics including social and environmental factors, clinical traits, and other novel risk factors to predict GDM prevention through interventions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37454979,
title = {HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44 Natural Killer Cells in Ulcerative Colitis},
author = {Martin E Baumdick and Annika Niehrs and Frauke Degenhardt and Maria Schwerk and Ole Hinrichs and Ana Jordan-Paiz and Benedetta Padoan and Lucy H M Wegner and Sebastian Schloer and Britta F Zecher and Jakob Malsy and Vinita R Joshi and Christin Illig and Jennifer Schröder-Schwarz and Kimberly J Möller and  and Maureen P Martin and Yuko Yuki and Mikki Ozawa and Jürgen Sauter and Alexander H Schmidt and Daniel Perez and Anastasios D Giannou and Mary Carrington and Randall S Davis and Udo Schumacher and Guido Sauter and Samuel Huber and Victor G Puelles and Nathaniel Melling and Andre Franke and  and Marcus Altfeld and Madeleine J Bunders},
doi = {10.1053/j.gastro.2023.06.034},
issn = {1528-0012},
year  = {2023},
date = {2023-10-01},
journal = {Gastroenterology},
volume = {165},
number = {4},
pages = {946--962.e13},
abstract = {BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.nnMETHODS: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.nnRESULTS: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401 individuals showed significantly stronger binding of NKp44 compared with HLA-DP301 IECs. HLA-DP401 IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44 NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301 organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.nnCONCLUSIONS: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44 NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44 NK cell-mediated destruction of the intestinal epithelium in UC.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37794109,
title = {Impact of individual and environmental factors on dietary or lifestyle interventions to prevent type 2 diabetes development: a systematic review},
author = {Dhanasekaran Bodhini and Robert W Morton and Vanessa Santhakumar and Mariam Nakabuye and Hugo Pomares-Millan and Christoffer Clemmensen and Stephanie L Fitzpatrick and Marta Guasch-Ferre and James S Pankow and Mathias Ried-Larsen and Paul W Franks and  and Deirdre K Tobias and Jordi Merino and Viswanathan Mohan and Ruth J F Loos},
doi = {10.1038/s43856-023-00363-0},
issn = {2730-664X},
year  = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {133},
abstract = {BACKGROUND: The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D.nnMETHODS: We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier.nnRESULTS: The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition.nnCONCLUSIONS: We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37263773,
title = {Children's cognitive performance and suicide risk through middle adulthood},
author = {Pablo Vidal-Ribas and Theemeshni Govender and Jing Yu and Rajeshwari Sundaram and Roy H Perlis and Stephen E Gilman},
doi = {10.1111/jcpp.13841},
issn = {1469-7610},
year  = {2023},
date = {2023-10-01},
journal = {J Child Psychol Psychiatry},
volume = {64},
number = {10},
pages = {1480--1491},
abstract = {BACKGROUND: Longitudinal studies show that lower cognitive performance in adolescence and early adulthood is associated with higher risk of suicide death throughout adulthood. However, it is unclear whether this cognitive vulnerability originates earlier in childhood since studies conducted in children are scarce and have inconsistent results.nnMETHODS: Vital status of 49,853 individuals born between 1959 and 1966 to participants in the Collaborative Perinatal Project cohort was determined by a probabilistic linkage to the National Death Index, covering all US deaths occurring from 1979 through 2016. Cox proportional hazard models were used to examine associations of general, verbal, and non-verbal intelligence at ages 4 and 7, and academic skills at age 7 with suicide death coded according to ICD-9/10 criteria, while accounting for sociodemographic and pregnancy factors previously associated with suicide in this sample.nnRESULTS: By the end of 2016, 288 cohort members had died by suicide. Cognitive performance at 7 years on tests with verbal components was associated with suicide risk (average vs. high verbal intelligence, HR = 1.97, 95% CI 1.05-3.71; low vs. high spelling skills, HR = 2.02, 95% CI 1.16-3.51; low vs. high reading skills, HR = 2.01, 95% CI 1.27-3.17). Associations were still evident, especially for verbal intelligence and reading skills, but hazard ratios were attenuated after adjusting for prenatal and sociodemographic factors at birth (verbal intelligence, HR = 1.97, 95% CI 1.03-3.78; spelling, HR = 1.61, 95% CI 0.90-2.88; reading, HR = 1.67, 95% CI 1.02-2.72).nnCONCLUSIONS: Childhood neurocognitive performance is associated with vulnerability to suicide mortality through middle-adulthood, suggesting that there might be a cognitive diathesis for suicide originating in early childhood. Future studies should examine how multiple domains of childhood cognitive performance contribute to vulnerability to suicide risk, including by increasing risk for social and environmental factors that are associated not only with suicide but also with many types of psychiatric disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37794166,
title = {Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review},
author = {Katherine G Young and Eram Haider McInnes and Robert J Massey and Anna R Kahkoska and Scott J Pilla and Sridharan Raghavan and Maggie A Stanislawski and Deirdre K Tobias and Andrew P McGovern and Adem Y Dawed and Angus G Jones and Ewan R Pearson and John M Dennis and },
doi = {10.1038/s43856-023-00359-w},
issn = {2730-664X},
year  = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {131},
abstract = {BACKGROUND: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.nnMETHODS: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.nnRESULTS: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.nnCONCLUSIONS: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37794169,
title = {Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review},
author = {Jamie L Felton and Kurt J Griffin and Richard A Oram and Cate Speake and S Alice Long and Suna Onengut-Gumuscu and Stephen S Rich and Gabriela S F Monaco and Carmella Evans-Molina and Linda A DiMeglio and Heba M Ismail and Andrea K Steck and Dana Dabelea and Randi K Johnson and Marzhan Urazbayeva and Stephen Gitelman and John M Wentworth and Maria J Redondo and Emily K Sims and },
doi = {10.1038/s43856-023-00357-y},
issn = {2730-664X},
year  = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {130},
abstract = {BACKGROUND: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification.nnMETHODS: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.nnRESULTS: We identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings.nnCONCLUSIONS: While the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37798471,
title = {Precision subclassification of type 2 diabetes: a systematic review},
author = {Shivani Misra and Robert Wagner and Bige Ozkan and Martin Schön and Magdalena Sevilla-Gonzalez and Katsiaryna Prystupa and Caroline C Wang and Raymond J Kreienkamp and Sara J Cromer and Mary R Rooney and Daisy Duan and Anne Cathrine Baun Thuesen and Amelia S Wallace and Aaron Leong and Aaron J Deutsch and Mette K Andersen and Liana K Billings and Robert H Eckel and Wayne Huey-Herng Sheu and Torben Hansen and Norbert Stefan and Mark O Goodarzi and Debashree Ray and Elizabeth Selvin and Jose C Florez and  and James B Meigs and Miriam S Udler},
doi = {10.1038/s43856-023-00360-3},
issn = {2730-664X},
year  = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {138},
abstract = {BACKGROUND: Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients.nnMETHODS: We searched PubMed and Embase for publications that used 'simple subclassification' approaches using simple categorisation of clinical characteristics, or 'complex subclassification' approaches which used machine learning or 'omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches.nnRESULTS: Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes.nnCONCLUSION: Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37787451,
title = {Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage},
author = {Livia Parodi and Mary E Comeau and Marios K Georgakis and Ernst Mayerhofer and Jaeyoon Chung and Guido J Falcone and Rainer Malik and Stacie L Demel and Bradford B Worrall and Sebastian Koch and Fernando D Testai and Steven J Kittner and Jacob L McCauley and Christiana E Hall and Douglas J Mayson and Mitchell Sv Elkind and Michael L James and Daniel Woo and Jonathan Rosand and Carl D Langefeld and Christopher D Anderson},
doi = {10.1002/ana.26814},
issn = {1531-8249},
year  = {2023},
date = {2023-10-01},
journal = {Ann Neurol},
abstract = {OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.nnMETHODS: 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44 and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.nnRESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.nnINTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and CSVD. This article is protected by copyright. All rights reserved.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37795593,
title = {Detection of Intracerebral Hemorrhage Using Low-Field, Portable Magnetic Resonance Imaging in Patients With Stroke},
author = {Mercy H Mazurek and Nethra R Parasuram and Teng J Peng and Rachel Beekman and Vineetha Yadlapalli and Annabel J Sorby-Adams and Dheeraj Lalwani and Julia Zabinska and Emily J Gilmore and Nils H Petersen and Guido J Falcone and Nanthiya Sujijantarat and Charles Matouk and Sam Payabvash and Gordon Sze and Steven J Schiff and Juan Eugenio Iglesias and Matthew S Rosen and Adam de Havenon and W Taylor Kimberly and Kevin N Sheth},
doi = {10.1161/STROKEAHA.123.043146},
issn = {1524-4628},
year  = {2023},
date = {2023-10-01},
journal = {Stroke},
abstract = {BACKGROUND: Neuroimaging is essential for detecting spontaneous, nontraumatic intracerebral hemorrhage (ICH). Recent data suggest ICH can be characterized using low-field magnetic resonance imaging (MRI). Our primary objective was to investigate the sensitivity and specificity of ICH on a 0.064T portable MRI (pMRI) scanner using a methodology that provided clinical information to inform rater interpretations. As a secondary aim, we investigated whether the incorporation of a deep learning (DL) reconstruction algorithm affected ICH detection.nnMETHODS: The pMRI device was deployed at Yale New Haven Hospital to examine patients presenting with stroke symptoms from October 26, 2020 to February 21, 2022. Three raters independently evaluated pMRI examinations. Raters were provided the images alongside the patient's clinical information to simulate real-world context of use. Ground truth was the closest conventional computed tomography or 1.5/3T MRI. Sensitivity and specificity results were grouped by DL and non-DL software to investigate the effects of software advances.nnRESULTS: A total of 189 exams (38 ICH, 89 acute ischemic stroke, 8 subarachnoid hemorrhage, 3 primary intraventricular hemorrhage, 51 no intracranial abnormality) were evaluated. Exams were correctly classified as positive or negative for ICH in 185 of 189 cases (97.9% overall accuracy). ICH was correctly detected in 35 of 38 cases (92.1% sensitivity). Ischemic stroke and no intracranial abnormality cases were correctly identified as blood-negative in 139 of 140 cases (99.3% specificity). Non-DL scans had a sensitivity and specificity for ICH of 77.8% and 97.1%, respectively. DL scans had a sensitivity and specificity for ICH of 96.6% and 99.3%, respectively.nnCONCLUSIONS: These results demonstrate improvements in ICH detection accuracy on pMRI that may be attributed to the integration of clinical information in rater review and the incorporation of a DL-based algorithm. The use of pMRI holds promise in providing diagnostic neuroimaging for patients with ICH.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37777983,
title = {Comparison between self-reported and actigraphy-derived sleep measures in patients receiving home parenteral nutrition: Secondary analysis of observational data},
author = {Adline Rahmoune and Marion F Winkler and Richa Saxena and Charlene Compher and Hassan S Dashti},
doi = {10.1002/ncp.11077},
issn = {1941-2452},
year  = {2023},
date = {2023-10-01},
journal = {Nutr Clin Pract},
abstract = {BACKGROUND: Patients receiving home parenteral nutrition (HPN) frequently report disrupted sleep. However, there are often inconsistencies between objectively measured and questionnaire-derived sleep measures. We compared sleep measures estimated from wrist actigraphy and self-report in adults receiving HPN.nnMETHODS: In this secondary analysis, we pooled data from two sleep-related studies enrolling adults receiving habitual HPN. We compared measures from 7-day averages of wrist actigraphy against comparable responses to a sleep questionnaire. Sleep measures included bedtime, wake time, time in bed, total sleep time, and sleep onset latency (SOL). Spearman correlation coefficients, Bland-Altman plots, and linear regression models for each set of sleep measures provided estimates of agreement.nnRESULTS: Participants (N = 35) had a mean age of 52 years, body mass index of 21.6 kg/m , and 77% identified as female. Correlation coefficients ranged from 0.35 to 0.90, were highest for wake time (r = 0.90) and bedtime (r = 0.74), and lowest for total sleep time (r = 0.35). Actigraphy overestimated self-reported bedtime, wake time, and total sleep time and underestimated self-reported time in bed and SOL. Regression coefficients indicated the highest calibration for bedtime and wake time and lower calibration for time in bed, total sleep time, and SOL.nnCONCLUSION: We observed strong-to-moderate agreement between sleep measures derived from wrist actigraphy and self-report in adults receiving HPN. Weaker correlations for total sleep time and SOL may indicate low wrist actigraphy sensitivity. Low-quality sleep resulting from sleep disruptions may have also contributed to an underreporting of perceived sleep quantity and lower concordance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37719664,
title = {Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate},
author = {Kelsey Robinson and Trenell J Mosley and Kenneth S Rivera-González and Christopher R Jabbarpour and Sarah W Curtis and Wasiu Lanre Adeyemo and Terri H Beaty and Azeez Butali and Carmen J Buxó and David J Cutler and Michael P Epstein and Lord J J Gowans and Jacqueline T Hecht and Jeffrey C Murray and Gary M Shaw and Lina Moreno Uribe and Seth M Weinberg and Harrison Brand and Mary L Marazita and Robert J Lipinski and Elizabeth J Leslie},
doi = {10.1016/j.xhgg.2023.100234},
issn = {2666-2477},
year  = {2023},
date = {2023-10-01},
journal = {HGG Adv},
volume = {4},
number = {4},
pages = {100234},
abstract = {Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n = 435), and subtype-specific risks for any cleft soft palate (CSP), (n = 259) and any cleft hard palate (CHP) (n = 125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p = 4.24 × 10) associated with CHP. One gene at this locus, angiopoietin-like 2 (), plays a role in osteoblast differentiation. It is expressed both in craniofacial tissue of human embryos and developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p < 5 × 10), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios for the 20 loci were most similar across all 3 groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either subtype. We also found nominal evidence of replication (p < 0.05) for 22 SNPs previously associated with orofacial clefts. Our study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37782501,
title = {Evaluating the Application of Large Language Models in Clinical Research Contexts},
author = {Roy H Perlis and Stephan D Fihn},
doi = {10.1001/jamanetworkopen.2023.35924},
issn = {2574-3805},
year  = {2023},
date = {2023-10-01},
journal = {JAMA Netw Open},
volume = {6},
number = {10},
pages = {e2335924},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37704630,
title = {Quantifying the causal impact of biological risk factors on healthcare costs},
author = {Jiwoo Lee and Sakari Jukarainen and Antti Karvanen and Padraig Dixon and Neil M Davies and George Davey Smith and Pradeep Natarajan and Andrea Ganna},
doi = {10.1038/s41467-023-41394-4},
issn = {2041-1723},
year  = {2023},
date = {2023-09-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {5672},
abstract = {Understanding the causal impact that clinical risk factors have on healthcare-related costs is critical to evaluate healthcare interventions. Here, we used a genetically-informed design, Mendelian Randomization (MR), to infer the causal impact of 15 risk factors on annual total healthcare costs. We calculated healthcare costs for 373,160 participants from the FinnGen Study and replicated our results in 323,774 individuals from the United Kingdom and Netherlands. Robust causal effects were observed for waist circumference (WC), adult body mass index, and systolic blood pressure, in which a standard deviation increase corresponded to 22.78% [95% CI: 18.75-26.95], 13.64% [10.26-17.12], and 13.08% [8.84-17.48] increased healthcare costs, respectively. A lack of causal effects was observed for certain clinically relevant biomarkers, such as albumin, C-reactive protein, and vitamin D. Our results indicated that increased WC is a major contributor to annual total healthcare costs and more attention may be given to WC screening, surveillance, and mitigation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37755830,
title = {Community Mobility and Depressive Symptoms During the COVID-19 Pandemic in the United States},
author = {Roy H Perlis and Kristin Lunz Trujillo and Alauna Safarpour and Alexi Quintana and Matthew D Simonson and Jasper Perlis and Mauricio Santillana and Katherine Ognyanova and Matthew A Baum and James N Druckman and David Lazer},
doi = {10.1001/jamanetworkopen.2023.34945},
issn = {2574-3805},
year  = {2023},
date = {2023-09-01},
journal = {JAMA Netw Open},
volume = {6},
number = {9},
pages = {e2334945},
abstract = {IMPORTANCE: Marked elevation in levels of depressive symptoms compared with historical norms have been described during the COVID-19 pandemic, and understanding the extent to which these are associated with diminished in-person social interaction could inform public health planning for future pandemics or other disasters.nnOBJECTIVE: To describe the association between living in a US county with diminished mobility during the COVID-19 pandemic and self-reported depressive symptoms, while accounting for potential local and state-level confounding factors.nnDESIGN, SETTING, AND PARTICIPANTS: This survey study used 18 waves of a nonprobability internet survey conducted in the United States between May 2020 and April 2022. Participants included respondents who were 18 years and older and lived in 1 of the 50 US states or Washington DC.nnMAIN OUTCOME AND MEASURE: Depressive symptoms measured by the Patient Health Questionnaire-9 (PHQ-9); county-level community mobility estimates from mobile apps; COVID-19 policies at the US state level from the Oxford stringency index.nnRESULTS: The 192 271 survey respondents had a mean (SD) of age 43.1 (16.5) years, and 768 (0.4%) were American Indian or Alaska Native individuals, 11 448 (6.0%) were Asian individuals, 20 277 (10.5%) were Black individuals, 15 036 (7.8%) were Hispanic individuals, 1975 (1.0%) were Pacific Islander individuals, 138 702 (72.1%) were White individuals, and 4065 (2.1%) were individuals of another race. Additionally, 126 381 respondents (65.7%) identified as female and 65 890 (34.3%) as male. Mean (SD) depression severity by PHQ-9 was 7.2 (6.8). In a mixed-effects linear regression model, the mean county-level proportion of individuals not leaving home was associated with a greater level of depression symptoms (β, 2.58; 95% CI, 1.57-3.58) after adjustment for individual sociodemographic features. Results were similar after the inclusion in regression models of local COVID-19 activity, weather, and county-level economic features, and persisted after widespread availability of COVID-19 vaccination. They were attenuated by the inclusion of state-level pandemic restrictions. Two restrictions, mandatory mask-wearing in public (β, 0.23; 95% CI, 0.15-0.30) and policies cancelling public events (β, 0.37; 95% CI, 0.22-0.51), demonstrated modest independent associations with depressive symptom severity.nnCONCLUSIONS AND RELEVANCE: In this study, depressive symptoms were greater in locales and times with diminished community mobility. Strategies to understand the potential public health consequences of pandemic responses are needed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37798224,
title = {Life-Course Brain Health as a Determinant of Late-Life Mental Health: American Association for Geriatric Psychiatry Expert Panel Recommendations},
author = {Harris A Eyre and Lucy E Stirland and Dilip V Jeste and Charles F Reynolds and Michael Berk and Agustin Ibanez and Walter D Dawson and Brian Lawlor and Iracema Leroi and Kristine Yaffe and Jennifer R Gatchel and Jordan F Karp and Paul Newhouse and Jonathan Rosand and Nicole Letourneau and Eleonore Bayen and Francesca Farina and Laura Booi and Devangere P Devanand and Jacobo Mintzer and Sheri Madigan and Inez Jayapurwala and Stephen T C Wong and Veronica Podence Falcoa and Jeffrey L Cummings and William Reichman and Sarah Lenz Lock and Marc Bennett and Rajiv Ahuja and David C Steffens and Mitchell S V Elkind and Helen Lavretsky},
doi = {10.1016/j.jagp.2023.09.013},
issn = {1545-7214},
year  = {2023},
date = {2023-09-01},
journal = {Am J Geriatr Psychiatry},
abstract = {This position statement of the Expert Panel on Brain Health of the American Association for Geriatric Psychiatry (AAGP) emphasizes the critical role of life course brain health in shaping mental well-being during the later stages of life. Evidence posits that maintaining optimal brain health earlier in life is crucial for preventing and managing brain aging-related disorders such as dementia/cognitive decline, depression, stroke, and anxiety. We advocate for a holistic approach that integrates medical, psychological, and social frameworks with culturally tailored interventions across the lifespan to promote brain health and overall mental well-being in aging adults across all communities. Furthermore, our statement underscores the significance of prevention, early detection, and intervention in identifying cognitive decline, mood changes, and related mental illness. Action should also be taken to understand and address the needs of communities that traditionally have unequal access to preventive health information and services. By implementing culturally relevant and tailored evidence-based practices and advancing research in geriatric psychiatry, behavioral neurology, and geroscience, we can enhance the quality of life for older adults facing the unique challenges of aging. This position statement emphasizes the intrinsic link between brain health and mental health in aging, urging healthcare professionals, policymakers, and a broader society to prioritize comprehensive strategies that safeguard and promote brain health from birth through later years across all communities. The AAGP Expert Panel has the goal of launching further activities in the coming months and years.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37775316,
title = {Interplay Between Chronic Kidney Disease, Hypertension, and Stroke: Insights From a Multivariable Mendelian Randomization Analysis},
author = {Dearbhla M Kelly and Marios K Georgakis and Nora Franceschini and Deborah Blacker and Anand Viswanathan and Christopher D Anderson},
doi = {10.1212/WNL.0000000000207852},
issn = {1526-632X},
year  = {2023},
date = {2023-09-01},
journal = {Neurology},
abstract = {BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) increases the risk of stroke, but the extent through which this association is mediated by hypertension is unknown. We leveraged large-scale genetic data to explore causal relationships between CKD, hypertension and cerebrovascular disease phenotypes.nnMETHODS: We used data from genome-wide association studies (GWAS) of European ancestry to identify genetic proxies for kidney function (CKD diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]), systolic blood pressure (SBP), and cerebrovascular disease (ischaemic stroke and its subtypes, and intracerebral haemorrhage [ICH). We then conducted univariable, multivariable and mediation Mendelian randomization (MR) analyses to investigate the effect of kidney function on stroke risk and the proportion of this effect mediated through hypertension.nnRESULTS: Univariable Mendelian randomization revealed associations between genetically determined lower eGFR and risk of all stroke (OR per 1-log decrement in eGFR, 1.77; 95% CI, 1.31-2.40; p<0.001), ischaemic stroke (OR, 1.81; 95% CI, 1.31-2.51; p<0.001), and most strongly with large artery stroke (LAS) (OR, 3.00; 95% CI, 1.33-6.75; p=0.008). These associations remained significant in the multivariable MR analysis, controlling for SBP (OR, 1.98; 95% CI, 1.39-2.82; p<0.001 for AS; OR, 2.16; 95% CI, 1.48-3.17; p<0.001 for IS; OR, 4.35; 95% CI, 1.84-10.27; p=0.001 for LAS), with only a small proportion of the total effects mediated by SBP (6.5% [0.7-16.8%], 6.6% [0.8-18.3%] and 7.2% [0.5-24.8%], respectively). Total, direct and indirect effect estimates were similar across a number of sensitivity analyses (Weighted median, MR-Egger regression).nnDISCUSSION: Our results demonstrate an independent causal effect of impaired kidney function, as assessed by decreased eGFR, on stroke risk, particularly LAS, even when controlled for SBP. Targeted prevention of kidney disease could lower atherosclerotic stroke risk independent of hypertension.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37023267,
title = {Evaluating the association between genetically proxied ACE inhibition and dementias},
author = {Malik Nassan and Iyas Daghlas and Ignazio S Piras and Emily Rogalski and Lianne M Reus and Yolande Pijnenburg and Leah K Cuddy and Richa Saxena and M-Marsel Mesulam and Matt Huentelman},
doi = {10.1002/alz.13062},
issn = {1552-5279},
year  = {2023},
date = {2023-09-01},
journal = {Alzheimers Dement},
volume = {19},
number = {9},
pages = {3894--3901},
abstract = {INTRODUCTION: Angiotensin-converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, the causal effect of ACE inhibition on risk of Alzheimer's disease (AD) dementia and other common dementias is largely unknown.nnMETHODS: We examined the causal association of genetically proxied ACE inhibition with four types of dementias using a two-sample Mendelian randomization (MR) approach.nnRESULTS: Genetically proxied ACE inhibition was associated with increased risk of AD dementia (odds ratio per one standard deviation reduction in serum ACE [95% confidence interval]; 1.07 [1.04-1.10], P = 5 × 10 ) and frontotemporal dementia (1.16 [1.04-1.29], P = 0.01) but not with Lewy body dementia or vascular dementia (P > 0.05). These findings were independently replicated and remained consistent in sensitivity analyses.nnDISCUSSION: This comprehensive MR study provided genetic evidence for an association between ACE inhibition and the risk for AD and frontotemporal dementias. These results should encourage further studies of the neurocognitive effects of ACE inhibition.nnHIGHLIGHTS: This study evaluated genetically proxied angiotensin-converting enzyme (ACE) inhibition association with dementias. The results suggest an association between ACE inhibition and Alzheimer's disease. The results suggest an association between ACE inhibition and frontotemporal dementia. Those associations can be interpreted as potentially causal.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37743782,
title = {De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia, seizures, gait abnormalities, and variable movement abnormalities},
author = {Scott K Ward and Alexandrea Wadley and Chun-Hui Anne Tsai and Paul J Benke and Lisa Emrick and Kristen Fisher and Kimberly M Houck and Hongzheng Dai and  and Maria J Guillen Sacoto and William Craigen and Kimberly Glaser and David R Murdock and Luis Rohena and Karin E M Diderich and Hennie T Bruggenwirth and Brendan Lee and Carlos Bacino and Lindsay C Burrage and Jill A Rosenfeld},
doi = {10.1002/ajmg.a.63399},
issn = {1552-4833},
year  = {2023},
date = {2023-09-01},
journal = {Am J Med Genet A},
abstract = {The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37694372,
title = {Age-Dependent Increase in Tau Phosphorylation at Serine 396 in Huntington's Disease Prefrontal Cortex},
author = {Tiziana Petrozziello and Sommer S Huntress and Ayleen L Castillo-Torres and James P Quinn and Theresa R Connors and Corinne A Auger and Alexandra N Mills and Spencer E Kim and Sophia Liu and Farah Mahmood and Adel Boudi and Muzhou Wu and Ellen Sapp and Pia Kivisäkk and Shekar R Sunderesh and Mahmoud A Pouladi and Steven E Arnold and Bradley T Hyman and H Diana Rosas and Marian DiFiglia and Ricardo Mouro Pinto and Kimberly Kegel-Gleason and Ghazaleh Sadri-Vakili},
doi = {10.3233/JHD-230588},
issn = {1879-6400},
year  = {2023},
date = {2023-09-01},
journal = {J Huntingtons Dis},
abstract = {BACKGROUND: To date, it is still controversial whether tau phosphorylation plays a role in Huntington's disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD postmortem brain and mouse models.nnOBJECTIVE: The goal of this study was to determine whether total tau and pTau levels are altered in HD.nnMETHODS: Immunohistochemistry, cellular fractionations, and western blots were used to measure tau and pTau levels in a large cohort of HD and control postmortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau in HttQ111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay.nnRESULTS: Our results revealed that, while there was no difference in tau or pTau levels in HD PFC compared to controls, tau phosphorylated at S396 levels were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, tau or pTau levels were not altered in HttQ111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls.nnCONCLUSIONS: Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37633279,
title = {Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data},
author = {Moriel Singer-Berk and Sanna Gudmundsson and Samantha Baxter and Eleanor G Seaby and Eleina England and Jordan C Wood and Rachel G Son and Nicholas A Watts and Konrad J Karczewski and Steven M Harrison and Daniel G MacArthur and Heidi L Rehm and Anne O'Donnell-Luria},
doi = {10.1016/j.ajhg.2023.08.005},
issn = {1537-6605},
year  = {2023},
date = {2023-09-01},
journal = {Am J Hum Genet},
volume = {110},
number = {9},
pages = {1496--1508},
abstract = {Predicted loss of function (pLoF) variants are often highly deleterious and play an important role in disease biology, but many pLoF variants may not result in loss of function (LoF). Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines' PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 genes associated with autosomal-recessive disease from the Genome Aggregation Database (gnomAD v.2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in a low proportion expressed across transcripts (pext) scored region, or the presence of cryptic in-frame splice rescues. Variants predicted to evade LoF or to be potential artifacts were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of pLoF variants predicted as likely not LoF/not LoF, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37674002,
title = {A second update on mapping the human genetic architecture of COVID-19},
author = { },
doi = {10.1038/s41586-023-06355-3},
issn = {1476-4687},
year  = {2023},
date = {2023-09-01},
journal = {Nature},
volume = {621},
number = {7977},
pages = {E7--E26},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37536382,
title = {Convergent imaging-transcriptomic evidence for disturbed iron homeostasis in Gilles de la Tourette syndrome},
author = {Ahmad Seif Kanaan and Dongmei Yu and Riccardo Metere and Andreas Schäfer and Torsten Schlumm and Berkin Bilgic and Alfred Anwander and Carol A Mathews and Jeremiah M Scharf and Kirsten Müller-Vahl and Harald E Möller},
doi = {10.1016/j.nbd.2023.106252},
issn = {1095-953X},
year  = {2023},
date = {2023-09-01},
journal = {Neurobiol Dis},
volume = {185},
pages = {106252},
abstract = {Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patients, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron‑sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms affecting receptor expression and long-term potentiation in the limbic subdivision. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37768666,
title = {Reattribution to Mind-Brain Processes and Recovery From Chronic Back Pain: A Secondary Analysis of a Randomized Clinical Trial},
author = {Yoni K Ashar and Mark A Lumley and Roy H Perlis and Conor Liston and Faith M Gunning and Tor D Wager},
doi = {10.1001/jamanetworkopen.2023.33846},
issn = {2574-3805},
year  = {2023},
date = {2023-09-01},
journal = {JAMA Netw Open},
volume = {6},
number = {9},
pages = {e2333846},
abstract = {IMPORTANCE: In primary chronic back pain (CBP), the belief that pain indicates tissue damage is both inaccurate and unhelpful. Reattributing pain to mind or brain processes may support recovery.nnOBJECTIVES: To test whether the reattribution of pain to mind or brain processes was associated with pain relief in pain reprocessing therapy (PRT) and to validate natural language-based tools for measuring patients' symptom attributions.nnDESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of clinical trial data analyzed natural language data from patients with primary CBP randomized to PRT, placebo injection control, or usual care control groups and treated in a US university research setting. Eligible participants were adults aged 21 to 70 years with CBP recruited from the community. Enrollment extended from 2017 to 2018, with the current analyses conducted from 2020 to 2022.nnINTERVENTIONS: PRT included cognitive, behavioral, and somatic techniques to support reattributing pain to nondangerous, reversible mind or brain causes. Subcutaneous placebo injection and usual care were hypothesized not to affect pain attributions.nnMAIN OUTCOMES AND MEASURES: At pretreatment and posttreatment, participants listed their top 3 perceived causes of pain in their own words (eg, football injury, bad posture, stress); pain intensity was measured as last-week average pain (0 to 10 rating, with 0 indicating no pain and 10 indicating greatest pain). The number of attributions categorized by masked coders as reflecting mind or brain processes were summed to yield mind-brain attribution scores (range, 0-3). An automated scoring algorithm was developed and benchmarked against human coder-derived scores. A data-driven natural language processing (NLP) algorithm identified the dimensional structure of pain attributions.nnRESULTS: We enrolled 151 adults (81 female [54%], 134 White [89%], mean [SD] age, 41.1 [15.6] years) reporting moderate severity CBP (mean [SD] intensity, 4.10 [1.26]; mean [SD] duration, 10.0 [8.9] years). At pretreatment, 41 attributions (10%) were categorized as mind- or brain-related across intervention conditions. PRT led to significant increases in mind- or brain-related attributions, with 71 posttreatment attributions (51%) in the PRT condition categorized as mind- or brain-related, as compared with 22 (8%) in control conditions (mind-brain attribution scores: PRT vs placebo, g = 1.95 [95% CI, 1.45-2.47]; PRT vs usual care, g = 2.06 [95% CI, 1.57-2.60]). Consistent with hypothesized PRT mechanisms, increases in mind-brain attribution score were associated with reductions in pain intensity at posttreatment (standardized β = -0.25; t127 = -2.06; P = .04) and mediated the effects of PRT vs control on 1-year follow-up pain intensity (β = -0.35 [95% CI, -0.07 to -0.63]; P = .05). The automated word-counting algorithm and human coder-derived scores achieved moderate and substantial agreement at pretreatment and posttreatment (Cohen κ = 0.42 and 0.68, respectively). The data-driven NLP algorithm identified a principal dimension of mind and brain vs biomechanical attributions, converging with hypothesis-driven analyses.nnCONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized trial, PRT increased attribution of primary CBP to mind- or brain-related causes. Increased mind-brain attribution was associated with reductions in pain intensity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37595579,
title = {Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies},
author = {Chelsea Lowther and Elise Valkanas and Jessica L Giordano and Harold Z Wang and Benjamin B Currall and Kathryn O'Keefe and Emma Pierce-Hoffman and Nehir E Kurtas and Christopher W Whelan and Stephanie P Hao and Ben Weisburd and Vahid Jalili and Jack Fu and Isaac Wong and Ryan L Collins and Xuefang Zhao and Christina A Austin-Tse and Emily Evangelista and Gabrielle Lemire and Vimla S Aggarwal and Diane Lucente and Laura D Gauthier and Charlotte Tolonen and Nareh Sahakian and Christine Stevens and Joon-Yong An and Shan Dong and Mary E Norton and Tippi C MacKenzie and Bernie Devlin and Kelly Gilmore and Bradford C Powell and Alicia Brandt and Francesco Vetrini and Michelle DiVito and Stephan J Sanders and Daniel G MacArthur and Jennelle C Hodge and Anne O'Donnell-Luria and Heidi L Rehm and Neeta L Vora and Brynn Levy and Harrison Brand and Ronald J Wapner and Michael E Talkowski},
doi = {10.1016/j.ajhg.2023.07.010},
issn = {1537-6605},
year  = {2023},
date = {2023-09-01},
journal = {Am J Hum Genet},
volume = {110},
number = {9},
pages = {1454--1469},
abstract = {Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37773507,
title = {Misinformation, Trust, and Use of Ivermectin and Hydroxychloroquine for COVID-19},
author = {Roy H Perlis and Kristin Lunz Trujillo and Jon Green and Alauna Safarpour and James N Druckman and Mauricio Santillana and Katherine Ognyanova and David Lazer},
doi = {10.1001/jamahealthforum.2023.3257},
issn = {2689-0186},
year  = {2023},
date = {2023-09-01},
journal = {JAMA Health Forum},
volume = {4},
number = {9},
pages = {e233257},
abstract = {IMPORTANCE: The COVID-19 pandemic has been notable for the widespread dissemination of misinformation regarding the virus and appropriate treatment.nnOBJECTIVE: To quantify the prevalence of non-evidence-based treatment for COVID-19 in the US and the association between such treatment and endorsement of misinformation as well as lack of trust in physicians and scientists.nnDESIGN, SETTING, AND PARTICIPANTS: This single-wave, population-based, nonprobability internet survey study was conducted between December 22, 2022, and January 16, 2023, in US residents 18 years or older who reported prior COVID-19 infection.nnMAIN OUTCOME AND MEASURE: Self-reported use of ivermectin or hydroxychloroquine, endorsing false statements related to COVID-19 vaccination, self-reported trust in various institutions, conspiratorial thinking measured by the American Conspiracy Thinking Scale, and news sources.nnRESULTS: A total of 13 438 individuals (mean [SD] age, 42.7 [16.1] years; 9150 [68.1%] female and 4288 [31.9%] male) who reported prior COVID-19 infection were included in this study. In this cohort, 799 (5.9%) reported prior use of hydroxychloroquine (527 [3.9%]) or ivermectin (440 [3.3%]). In regression models including sociodemographic features as well as political affiliation, those who endorsed at least 1 item of COVID-19 vaccine misinformation were more likely to receive non-evidence-based medication (adjusted odds ratio [OR], 2.86; 95% CI, 2.28-3.58). Those reporting trust in physicians and hospitals (adjusted OR, 0.74; 95% CI, 0.56-0.98) and in scientists (adjusted OR, 0.63; 95% CI, 0.51-0.79) were less likely to receive non-evidence-based medication. Respondents reporting trust in social media (adjusted OR, 2.39; 95% CI, 2.00-2.87) and in Donald Trump (adjusted OR, 2.97; 95% CI, 2.34-3.78) were more likely to have taken non-evidence-based medication. Individuals with greater scores on the American Conspiracy Thinking Scale were more likely to have received non-evidence-based medications (unadjusted OR, 1.09; 95% CI, 1.06-1.11; adjusted OR, 1.10; 95% CI, 1.07-1.13).nnCONCLUSIONS AND RELEVANCE: In this survey study of US adults, endorsement of misinformation about the COVID-19 pandemic, lack of trust in physicians or scientists, conspiracy-mindedness, and the nature of news sources were associated with receiving non-evidence-based treatment for COVID-19. These results suggest that the potential harms of misinformation may extend to the use of ineffective and potentially toxic treatments in addition to avoidance of health-promoting behaviors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37669985,
title = {Demonstrating paths for unlocking the value of cloud genomics through cross cohort analysis},
author = {Nicole Deflaux and Margaret Sunitha Selvaraj and Henry Robert Condon and Kelsey Mayo and Sara Haidermota and Melissa A Basford and Chris Lunt and Anthony A Philippakis and Dan M Roden and Joshua C Denny and Anjene Musick and Rory Collins and Naomi Allen and Mark Effingham and David Glazer and Pradeep Natarajan and Alexander G Bick},
doi = {10.1038/s41467-023-41185-x},
issn = {2041-1723},
year  = {2023},
date = {2023-09-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {5419},
abstract = {Recently, large scale genomic projects such as All of Us and the UK Biobank have introduced a new research paradigm where data are stored centrally in cloud-based Trusted Research Environments (TREs). To characterize the advantages and drawbacks of different TRE attributes in facilitating cross-cohort analysis, we conduct a Genome-Wide Association Study of standard lipid measures using two approaches: meta-analysis and pooled analysis. Comparison of full summary data from both approaches with an external study shows strong correlation of known loci with lipid levels (R ~ 83-97%). Importantly, 90 variants meet the significance threshold only in the meta-analysis and 64 variants are significant only in pooled analysis, with approximately 20% of variants in each of those groups being most prevalent in non-European, non-Asian ancestry individuals. These findings have important implications, as technical and policy choices lead to cross-cohort analyses generating similar, but not identical results, particularly for non-European ancestral populations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36806881,
title = {Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma},
author = {Srirupa Bhattacharyya and Janet L Oblinger and Roberta L Beauchamp and Zhenzhen Yin and Serkan Erdin and Priya Koundinya and Anna D Ware and Marc Ferrer and Justin T Jordan and Scott R Plotkin and Lei Xu and Long-Sheng Chang and Vijaya Ramesh},
doi = {10.1093/neuonc/noad037},
issn = {1523-5866},
year  = {2023},
date = {2023-09-01},
journal = {Neuro Oncol},
volume = {25},
number = {9},
pages = {1617--1630},
abstract = {BACKGROUND: Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies.nnMETHODS: Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2-/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models.nnRESULTS: Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential.nnCONCLUSIONS: This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37751738,
title = {PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects},
author = {Florence Petit and Mauro Longoni and Julie Wells and Richard S Maser and Eric L Bogenschutz and Matthew J Dysart and Hannah T M Contreras and Frederic Frénois and Barbara R Pober and Robin D Clark and Philip F Giampietro and Hilger H Ropers and Hao Hu and Maria Loscertales and Richard Wagner and Xingbin Ai and Harrison Brand and Anne-Sophie Jourdain and Marie-Ange Delrue and Brigitte Gilbert-Dussardier and Louise Devisme and Boris Keren and David J McCulley and Lu Qiao and Rebecca Hernan and Julia Wynn and Tiana M Scott and Daniel G Calame and Zeynep Coban-Akdemir and Patricia Hernandez and Andres Hernandez-Garcia and Hagith Yonath and James R Lupski and Yufeng Shen and Wendy K Chung and Daryl A Scott and Carol J Bult and Patricia K Donahoe and Frances A High},
doi = {10.1016/j.ajhg.2023.09.002},
issn = {1537-6605},
year  = {2023},
date = {2023-09-01},
journal = {Am J Hum Genet},
abstract = {Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37745481,
title = {Click editing enables programmable genome writing using DNA polymerases and HUH endonucleases},
author = {Joana Ferreira da Silva and Connor J Tou and Emily M King and Madeline L Eller and Linyuan Ma and David Rufino-Ramos and Benjamin P Kleinstiver},
doi = {10.1101/2023.09.12.557440},
year  = {2023},
date = {2023-09-01},
journal = {bioRxiv},
abstract = {Genome editing technologies that install diverse edits can widely enable genetic studies and new therapeutics. Here we develop click editing, a genome writing platform that couples the advantageous properties of DNA-dependent DNA polymerases with RNA-programmable nickases (e.g. CRISPR-Cas) to permit the installation of a range of edits including substitutions, insertions, and deletions. Click editors (CEs) leverage the "click"-like bioconjugation ability of HUH endonucleases (HUHes) with single stranded DNA substrates to covalently tether "click DNA" (clkDNA) templates encoding user-specifiable edits at targeted genomic loci. Through iterative optimization of the modular components of CEs (DNA polymerase and HUHe orthologs, architectural modifications, etc.) and their clkDNAs (template configurations, repair evading substitutions, etc.), we demonstrate the ability to install precise genome edits with minimal indels and no unwanted byproduct insertions. Since clkDNAs can be ordered as simple DNA oligonucleotides for cents per base, it is possible to screen many different clkDNA parameters rapidly and inexpensively to maximize edit efficiency. Together, click editing is a precise and highly versatile platform for modifying genomes with a simple workflow and broad utility across diverse biological applications.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37486637,
title = {Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria},
author = {Shyam K Akula and Allen Y Chen and Jennifer E Neil and Diane D Shao and Alisa Mo and Norma K Hylton and Stephanie DiTroia and Vijay S Ganesh and Richard S Smith and Katherine O'Kane and Rebecca C Yeh and Jack H Marciano and Samantha Kirkham and Connor J Kenny and Janet H T Song and Muna Al Saffar and Francisca Millan and David J Harris and Andrea V Murphy and Kara C Klemp and Stephen R Braddock and Harrison Brand and Isaac Wong and Michael E Talkowski and Anne O'Donnell-Luria and Abbe Lai and Robert Sean Hill and Ganeshwaran H Mochida and Ryan N Doan and A James Barkovich and Edward Yang and Dina Amrom and Eva Andermann and Annapurna Poduri and Christopher A Walsh and },
doi = {10.1001/jamaneurol.2023.2363},
issn = {2168-6157},
year  = {2023},
date = {2023-09-01},
journal = {JAMA Neurol},
volume = {80},
number = {9},
pages = {980--988},
abstract = {IMPORTANCE: Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases.nnOBJECTIVE: To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations.nnDESIGN, SETTING, AND PARTICIPANTS: This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control.nnMAIN OUTCOMES AND MEASURES: The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed.nnRESULTS: In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families.nnCONCLUSIONS AND RELEVANCE: This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37776659,
title = {Monogenic Causes of Cerebrovascular Disease in Childhood: A Case Series},
author = {Bridget E L Ostrem and Deena Godfrey and Paul A Caruso and Patricia L Musolino},
doi = {10.1016/j.pediatrneurol.2023.08.026},
issn = {1873-5150},
year  = {2023},
date = {2023-09-01},
journal = {Pediatr Neurol},
volume = {149},
pages = {39--43},
abstract = {BACKGROUND: Despite an increase in the number of genes associated with pediatric stroke, imaging phenotypes in children have not been well reported. Guidelines are needed to facilitate the identification and treatment of patients with monogenic causes of cerebrovascular disorders.nnMETHODS: We performed a retrospective review of imaging and medical records of patients aged zero to 21 years with monogenic causes of vascular malformations, small or large vessel disease, transient ischemic attacks, and/or ischemic or hemorrhagic stroke. We classified patients according to their imaging phenotype and reviewed neurological and systemic features and management strategies. We reviewed the literature to identify genes associated with cerebrovascular disorders presenting in childhood.nnRESULTS: We identified 18 patients with monogenic causes of cerebrovascular disorders and classified each patient as belonging to one or more of three cerebrovascular phenotypes according to predominant imaging characteristics: small vessel disease, large vessel disease, and/or vascular malformations. Preventative treatments included aspirin, N-acetylcysteine, tocilizumab, therapeutic low-molecular-weight heparin, and resection of vascular malformations.nnCONCLUSIONS: Classifying pediatric patients with cerebrovascular disorders by imaging phenotype can aid in determining the next steps in genetic testing and treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37705717,
title = {Brain imaging with portable low-field MRI},
author = {W Taylor Kimberly and Annabel J Sorby-Adams and Andrew G Webb and Ed X Wu and Rachel Beekman and Ritvij Bowry and Steven J Schiff and Adam de Havenon and Francis X Shen and Gordon Sze and Pamela Schaefer and Juan Eugenio Iglesias and Matthew S Rosen and Kevin N Sheth},
doi = {10.1038/s44222-023-00086-w},
issn = {2731-6092},
year  = {2023},
date = {2023-09-01},
journal = {Nat Rev Bioeng},
volume = {1},
number = {9},
pages = {617--630},
abstract = {The advent of portable, low-field MRI (LF-MRI) heralds new opportunities in neuroimaging. Low power requirements and transportability have enabled scanning outside the controlled environment of a conventional MRI suite, enhancing access to neuroimaging for indications that are not well suited to existing technologies. Maximizing the information extracted from the reduced signal-to-noise ratio of LF-MRI is crucial to developing clinically useful diagnostic images. Progress in electromagnetic noise cancellation and machine learning reconstruction algorithms from sparse -space data as well as new approaches to image enhancement have now enabled these advancements. Coupling technological innovation with bedside imaging creates new prospects in visualizing the healthy brain and detecting acute and chronic pathological changes. Ongoing development of hardware, improvements in pulse sequences and image reconstruction, and validation of clinical utility will continue to accelerate this field. As further innovation occurs, portable LF-MRI will facilitate the democratization of MRI and create new applications not previously feasible with conventional systems.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37732255,
title = {Polygenic Scores for Longitudinal Prediction of Incident Type 2 Diabetes in an Ancestrally and Medically Diverse Primary Care Network},
author = {Ravi Mandla and Philip Schroeder and Bianca Porneala and Jose C Florez and James B Meigs and Josep M Mercader and Aaron Leong},
doi = {10.1101/2023.09.08.23295276},
year  = {2023},
date = {2023-09-01},
journal = {medRxiv},
abstract = {OBJECTIVE: The clinical utility of genetic information for type 2 diabetes (T2D) prediction with polygenic score (PGS) in ancestrally diverse, real-world US healthcare systems is unclear, especially for those at low clinical phenotypic risk for T2D.nnRESEARCH DESIGN AND METHODS: We tested the association of PGS with T2D incidence in patients followed within a primary care practice network over 16 years in four hypothetical scenarios that varied by clinical data availability (N = 14,712): 1) age and sex, 2) age, sex, BMI, systolic blood pressure, and family history of diabetes; 3) all variables in (2) and random glucose; 4) all variables in (3), HDL, total cholesterol, and triglycerides, combined in a clinical risk score (CRS). To determine whether genetic effects differed by baseline clinical risk, we tested for interaction with the CRS.nnRESULTS: PGS was associated with incident diabetes in all models. Adjusting for age and sex only, the Hazard Ratio (HR) per PGS standard deviation (SD) was 1.76 (95% CI 1.68, 1.84) and the HR of top 5% of PGS vs interquartile range (IQR) was 2.80 (2.39, 3.28). Adjusting for the CRS, the HR per SD was 1.48 (1.40, 1.57) and HR of top 5% of PGS vs IQR was 2.09 (1.72, 2.55). Genetic effects differed by baseline clinical risk [(PGS-CRS interaction  =0.05; CRS below the median: HR 1.60 (1.43, 1.79); CRS above the median: HR 1.45 (1.35, 1.55)].nnCONCLUSIONS: Genetic information can help identify high-risk patients even among those perceived to be low risk in a clinical evaluation.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37730292,
title = {Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors: JACC State-of-the-Art Review},
author = {Gemma A Figtree and Stephen T Vernon and Jason A Harmer and Michael P Gray and Clare Arnott and Eric Bachour and Giannie Barsha and David Brieger and Alex Brown and David S Celermajer and Keith M Channon and Nicholas W S Chew and James J H Chong and Clara K Chow and Peter A Cistulli and Patrick T Ellinor and Stuart M Grieve and Tomasz J Guzik and Emil Hagström and Alicia Jenkins and Garry Jennings and Anthony C Keech and Katharine A Kott and Leonard Kritharides and Mamas A Mamas and Roxana Mehran and Peter J Meikle and Pradeep Natarajan and Kazuaki Negishi and John O'Sullivan and Sanjay Patel and Peter J Psaltis and Julie Redfern and Philippe G Steg and David R Sullivan and Johan Sundström and Birgit Vogel and Andrew Wilson and Dennis Wong and Deepak L Bhatt and Jason C Kovacic and Stephen J Nicholls and },
doi = {10.1016/j.jacc.2023.06.045},
issn = {1558-3597},
year  = {2023},
date = {2023-09-01},
journal = {J Am Coll Cardiol},
volume = {82},
number = {13},
pages = {1343--1359},
abstract = {Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37661008,
title = {Beyond the Global Brain Differences: Intra-individual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers},
author = {Rune Boen and Tobias Kaufmann and Dennis van der Meer and Oleksandr Frei and Ingrid Agartz and David Ames and Micael Andersson and Nicola J Armstrong and Eric Artiges and Joshua R Atkins and Jochen Bauer and Francesco Benedetti and Dorret I Boomsma and Henry Brodaty and Katharina Brosch and Randy L Buckner and Murray J Cairns and Vince Calhoun and Svenja Caspers and Sven Cichon and Aiden P Corvin and Benedicto Crespo Facorro and Udo Dannlowski and Friederike S David and Eco J C de Geus and Greig I de Zubicaray and Sylvane Desrivières and Joanne L Doherty and Gary Donohoe and Stefan Ehrlich and Else Eising and Thomas Espeseth and Simon E Fisher and Andreas J Forstner and Lidia Fortaner Uyà and Vincent Frouin and Masaki Fukunaga and Tian Ge and David C Glahn and Janik Goltermann and Hans J Grabe and Melissa J Green and Nynke A Groenewold and Dominik Grotegerd and Tim Hahn and Ryota Hashimoto and Jayne Y Hehir-Kwa and Frans A Henskens and Avram J Holmes and Asta K Haberg and Jan Haavik and Sebastien Jacquemont and Andreas Jansen and Christiane Jockwitz and Erik G Jonsson and Masataka Kikuchi and Tilo Kircher and Kuldeep Kumar and Stephanie Le Hellard and Costin Leu and David E Linden and Jingyu Liu and Robert Loughnan and Karen A Mather and Katie L McMahon and Allan F McRae and Sarah E Medland and Susanne Meinert and Clara A Moreau and Derek W Morris and Bryan J Mowry and Thomas W Muhleisen and Igor Nenadić and Markus M Nöthen and Lars Nyberg and Michael J Owen and Marco Paolini and Tomas Paus and Zdenka Pausova and Karin Persson and Yann Quidé and Tiago Reis Marques and Perminder S Sachdev and Sigrid B Sando and Ulrich Schall and Rodney J Scott and Geir Selbæk and Elena Shumskaya and Ana I Silva and Sanjay M Sisodiya and Frederike Stein and Dan J Stein and Benjamin Straube and Fabian Streit and Lachlan T Strike and Alexander Teumer and Lea Teutenberg and Anbupalam Thalamuthu and Paul A Tooney and Diana Tordesillas-Gutierrez and Julian N Trollor and Dennis van 't Ent and Marianne B M van den Bree and Neeltje E M van Haren and Javier Vazquez-Bourgon and Henry Volzke and Wei Wen and Katharina Wittfeld and Christopher R K Ching and Lars T Westlye and Paul M Thompson and Carrie E Bearden and Kaja K Selmer and Dag Alnæs and Ole A Andreassen and Ida E Sonderby},
doi = {10.1016/j.biopsych.2023.08.018},
issn = {1873-2402},
year  = {2023},
date = {2023-09-01},
journal = {Biol Psychiatry},
abstract = {BACKGROUND: The 1q21.1 distal and 15q11.2 BP1-BP2 CNVs exhibit regional and global brain differences compared to non-carriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intra-individual variability measures can be used to test for regional differences beyond global differences in brain structure.nnMETHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n=30) and duplication (n=27), and 15q11.2 BP1-BP2 deletion (n=170) and duplication (n=243) carriers and matched non-carriers (n=2,350). Regional intra-deviation (RID) scores i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference.nnRESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate and temporal pole differed less, and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex and temporal pole differed less, and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.nnCONCLUSION: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 CNVs. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 CNVs, with the potential to increase our understanding of mechanisms involved in altered neurodevelopment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37566941,
title = {Sex-specific impact of maternal obesity on fetal placental macrophages and cord blood triglycerides},
author = {Lydia L Shook and Kaitlyn E James and Drucilla J Roberts and Camille E Powe and Roy H Perlis and Kent L Thornburg and Perrie F O'Tierney-Ginn and Andrea G Edlow},
doi = {10.1016/j.placenta.2023.08.001},
issn = {1532-3102},
year  = {2023},
date = {2023-09-01},
journal = {Placenta},
volume = {140},
pages = {100--108},
abstract = {INTRODUCTION: Maternal obesity is associated with increased risk of offspring obesity and cardiometabolic disease. Altered fetoplacental immune programming is a potential candidate mechanism. Differences in fetal placental macrophages, or Hofbauer cells (HBCs), have been observed in maternal obesity, and lipid metabolism is a key function of resident macrophages that may be deranged in inflammation/immune activation. We sought to test the following hypotheses: 1) maternal obesity is associated with altered HBC density and phenotype in the term placenta and 2) obesity-associated HBC changes are associated with altered placental lipid transport to the fetus. The impact of fetal sex was evaluated in all experiments.nnMETHODS: We quantified the density and morphology of CD163-and CD68-positive HBCs in placental villi in 34 full-term pregnancies undergoing cesarean delivery (N = 15, maternal BMI ≥30 kg/m; N = 19, BMI <30 kg/m). Antibody-positive cells in terminal villi were detected and cell size and circularity analyzed using a semi-automated method for thresholding of bright-field microscopy images (ImageJ). Placental expression of lipid transporter genes was quantified using RTqPCR, and cord plasma triglycerides (TGs) were profiled using modified Wahlefeld method. The impact of maternal obesity and fetal sex on HBC features, lipid transporters, and cord TGs were evaluated by two-way ANOVA. Spearman correlations of cord TGs, HBC metrics and gene expression levels were calculated.nnRESULTS: Maternal obesity was associated with significantly increased density of HBCs, with male placentas most affected (fetal sex by maternal obesity interaction p = 0.04). CD163+ HBCs were larger and rounder in obesity-exposed male placentas. Sexually dimorphic expression of placental FATP4, FATP6, FABPPM, AMPKB1 and AMPKG and cord TGs was noted in maternal obesity, such that levels were higher in males and lower in females relative to sex-matched controls. Cord TGs were positively correlated with HBC density and FATP1 expression.nnDISCUSSION: Maternal obesity is associated with sex-specific alterations in HBC density and placental lipid transporter expression, which may impact umbilical cord blood TG levels and offspring cardiometabolic programming.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37582364,
title = {Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma},
author = {Mark D Benson and Aaron S Eisman and Usman A Tahir and Daniel H Katz and Shuliang Deng and Debby Ngo and Jeremy M Robbins and Alissa Hofmann and Xu Shi and Shuning Zheng and Michelle Keyes and Zhi Yu and Yan Gao and Laurie Farrell and Dongxiao Shen and Zsu-Zsu Chen and Daniel E Cruz and Mario Sims and Adolfo Correa and Russell P Tracy and Peter Durda and Kent D Taylor and Yongmei Liu and W Craig Johnson and Xiuqing Guo and Jie Yao and Yii-Der Ida Chen and Ani W Manichaikul and Deepti Jain and Qiong Yang and  and Claude Bouchard and Mark A Sarzynski and Stephen S Rich and Jerome I Rotter and Thomas J Wang and James G Wilson and Clary B Clish and Indra Neil Sarkar and Pradeep Natarajan and Robert E Gerszten},
doi = {10.1016/j.cmet.2023.07.012},
issn = {1932-7420},
year  = {2023},
date = {2023-09-01},
journal = {Cell Metab},
volume = {35},
number = {9},
pages = {1646--1660.e3},
abstract = {Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37732265,
title = {Algorithms for the identification of prevalent diabetes in the All of Us Research Program validated using polygenic scores - a new resource for diabetes precision medicine},
author = {Lukasz Szczerbinski and Ravi Mandla and Philip Schroeder and Bianca C Porneala and Josephine H Li and Jose C Florez and Josep M Mercader and Alisa K Manning and Miriam S Udler},
doi = {10.1101/2023.09.05.23295061},
year  = {2023},
date = {2023-09-01},
journal = {medRxiv},
abstract = {OBJECTIVE: The study aimed to develop and validate algorithms for identifying people with type 1 and type 2 diabetes in the All of Us Research Program (AoU) cohort, using electronic health record (EHR) and survey data.nnRESEARCH DESIGN AND METHODS: Two sets of algorithms were developed, one using only EHR data (EHR), and the other using a combination of EHR and survey data (EHR+). Their performance was evaluated by testing their association with polygenic scores for both type 1 and type 2 diabetes.nnRESULTS: For type 1 diabetes, the EHR-only algorithm showed a stronger association with T1D polygenic score (  =3×10  ) than the EHR+. For type 2 diabetes, the EHR+ algorithm outperformed both the EHR-only and the existing AoU definition, identifying additional cases (25.79% and 22.57% more, respectively) and showing stronger association with T2D polygenic score (DeLong  =0.03 and 1×10  , respectively).nnCONCLUSIONS: We provide new validated definitions of type 1 and type 2 diabetes in AoU, and make them available for researchers. These algorithms, by ensuring consistent diabetes definitions, pave the way for high-quality diabetes research and future clinical discoveries.nnARTICLE HIGHLIGHTS:  a.This study was conducted to develop and validate algorithms for identifying type 1 and type 2 diabetes cases in the All of Us Research Program (AoU). b.Can accurate algorithms for type 1 and type 2 diabetes identification be developed and validated using AoU cohort Electronic Health Record (EHR) and survey data? Do the identified diabetes cases show association with polygenic scores in diverse populations? c.We developed a new validated type 1 diabetes definition and expanded upon the existing type 2 diabetes definition. d.The developed algorithms can be universally implemented in AoU for identifying study participants for well-defined case-control diabetes studies.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37767980,
title = {Managing Patients With Unlabeled Passive Implants on MR Systems Operating Below 1.5 T},
author = {Frank G Shellock and Matthew S Rosen and Andrew Webb and W Taylor Kimberly and Sunder Rajan and Aleksandar N Nacev and John V Crues},
doi = {10.1002/jmri.29002},
issn = {1522-2586},
year  = {2023},
date = {2023-09-01},
journal = {J Magn Reson Imaging},
abstract = {The standard of care for managing a patient with an implant is to identify the item and to assess the relative safety of scanning the patient. Because the 1.5 T MR system is the most prevalent scanner in the world and 3 T is the highest field strength in widespread use, implants typically have "MR Conditional" (i.e., an item with demonstrated safety in the MR environment within defined conditions) labeling at 1.5 and/or 3 T only. This presents challenges for a facility that has a scanner operating at a field strength below 1.5 T when encountering a patient with an implant, because scanning the patient is considered "off-label." In this case, the supervising physician is responsible for deciding whether to scan the patient based on the risks associated with the implant and the benefit of magnetic resonance imaging (MRI). For a passive implant, the MRI safety-related concerns are static magnetic field interactions (i.e., force and torque) and radiofrequency (RF) field-induced heating. The worldwide utilization of scanners operating below 1.5 T combined with the increasing incidence of patients with implants that need MRI creates circumstances that include patients potentially being subjected to unsafe imaging conditions or being denied access to MRI because physicians often lack the knowledge to perform an assessment of risk vs. benefit. Thus, physicians must have a complete understanding of the MRI-related safety issues that impact passive implants when managing patients with these products on scanners operating below 1.5 T. This monograph provides an overview of the various clinical MR systems operating below 1.5 T and discusses the MRI-related factors that influence safety for passive implants. Suggestions are provided for the management of patients with passive implants labeled MR Conditional at 1.5 and/or 3 T, referred to scanners operating below 1.5 T. The purpose of this information is to empower supervising physicians with the essential knowledge to perform MRI exams confidently and safely in patients with passive implants. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37600483,
title = {Comparative effectiveness of decompressive craniectomy versus craniotomy for traumatic acute subdural hematoma (CENTER-TBI): an observational cohort study},
author = {Thomas A van Essen and Inge A M van Erp and Hester F Lingsma and Dana Pisică and John K Yue and Ranjit D Singh and Jeroen T J M van Dijck and Victor Volovici and Alexander Younsi and Angelos Kolias and Lianne D Peppel and Majanka Heijenbrok-Kal and Gerard M Ribbers and David K Menon and Peter J A Hutchinson and Geoffrey T Manley and Bart Depreitere and Ewout W Steyerberg and Andrew I R Maas and Godard C W de Ruiter and Wilco C Peul and },
doi = {10.1016/j.eclinm.2023.102161},
issn = {2589-5370},
year  = {2023},
date = {2023-09-01},
journal = {EClinicalMedicine},
volume = {63},
pages = {102161},
abstract = {BACKGROUND: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy.nnMETHODS: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014-2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582).nnFINDINGS: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12-26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7,  < 0.0001). Higher centre preference for DC over craniotomy was not associated with better functional outcome (adjusted common odds ratio (OR) per 14% [IQR increase] more DC in a centre = 0.9 [95% CI 0.7-1.1], n = 200). Primary DC was associated with more follow-on surgeries and complications [secondary cranial surgery 27% vs. 18%; shunts 11 vs. 5%]; and similar odds of in-hospital mortality (adjusted OR per 14% IQR more primary DC 1.3 [95% CI (1.0-3.4), n = 200]).nnINTERPRETATION: We found substantial practice variation in the employment of DC over craniotomy for ASDH. This variation in treatment strategy did not result in different functional outcome. These findings suggest that primary DC should be restricted to salvageable patients in whom immediate replacement of the bone flap is not possible due to intraoperative brain swelling.nnFUNDING: Hersenstichting Nederland for the Dutch NeuroTraumatology Quality Registry and the European Union Seventh Framework Program.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37640881,
title = {Extremely sparse models of linkage disequilibrium in ancestrally diverse association studies},
author = {Pouria Salehi Nowbandegani and Anthony Wilder Wohns and Jenna L Ballard and Eric S Lander and Alex Bloemendal and Benjamin M Neale and Luke J O'Connor},
doi = {10.1038/s41588-023-01487-8},
issn = {1546-1718},
year  = {2023},
date = {2023-09-01},
journal = {Nat Genet},
volume = {55},
number = {9},
pages = {1494--1502},
abstract = {Linkage disequilibrium (LD) is the correlation among nearby genetic variants. In genetic association studies, LD is often modeled using large correlation matrices, but this approach is inefficient, especially in ancestrally diverse studies. In the present study, we introduce LD graphical models (LDGMs), which are an extremely sparse and efficient representation of LD. LDGMs are derived from genome-wide genealogies; statistical relationships among alleles in the LDGM correspond to genealogical relationships among haplotypes. We published LDGMs and ancestry-specific LDGM precision matrices for 18 million common variants (minor allele frequency >1%) in five ancestry groups, validated their accuracy and demonstrated order-of-magnitude improvements in runtime for commonly used LD matrix computations. We implemented an extremely fast multiancestry polygenic prediction method, BLUPx-ldgm, which performs better than a similar method based on the reference LD correlation matrix. LDGMs will enable sophisticated methods that scale to ancestrally diverse genetic association data across millions of variants and individuals.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37698481,
title = {Biometric magnetic resonance imaging analysis of fetal brain development in down syndrome},
author = {Rie Kitano and Neel Madan and Takahisa Mikami and Rajeevi Madankumar and Brian G Skotko and Stephanie Santoro and Steven J Ralston and Diana W Bianchi and Tomo Tarui},
doi = {10.1002/pd.6436},
issn = {1097-0223},
year  = {2023},
date = {2023-09-01},
journal = {Prenat Diagn},
abstract = {OBJECTIVES: To assess brain development in living fetuses with Down syndrome (DS) by biometric measurements on fetal brain magnetic resonance images (MRI).nnMETHODS: We scanned 10 MRIs of fetuses with confirmed trisomy 21 at birth and 12 control fetal MRIs without any detected anomalies. Fetal brain MRIs were analyzed using 14 fetal brain and skull biometric parameters. We compared measures between DS and controls in both raw MRIs and motion-corrected and anterior-posterior commissure-aligned images.nnRESULTS: In the reconstructed images, the measured values of the height of the cerebellar vermis (HV) and anteroposterior diameter of the cerebellar vermis (APDV) were significantly smaller, and the anteroposterior diameter of the fourth ventricle (APDF) was significantly larger in fetuses with DS than controls. In the raw MRIs, the measured values of the right lateral ventricle were significantly larger in fetuses with DS than in controls. Logistic regression analyses revealed that a new parameter, the cerebellar-to-fourth-ventricle ratio (i.e., (APDV * Height of the vermis)/APDF), was significantly smaller in fetuses with DS than controls and was the most predictive to distinguish between fetuses with DS and controls.nnCONCLUSIONS: The study revealed that fetuses with DS have smaller cerebellums and larger fourth ventricles compared to the controls.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37585212,
title = {Representation of Race and Ethnicity in the Contemporary US Health Cohort All of Us Research Program},
author = {Nina Kathiresan and So Mi Jemma Cho and Romit Bhattacharya and Buu Truong and Whitney Hornsby and Pradeep Natarajan},
doi = {10.1001/jamacardio.2023.2411},
issn = {2380-6591},
year  = {2023},
date = {2023-09-01},
journal = {JAMA Cardiol},
volume = {8},
number = {9},
pages = {859--864},
abstract = {IMPORTANCE: To address systemic disparities in biomedical research, the All of Us (AoU) Research Program was created to identify the root causes and consequences of health outcomes in the US. However, the extent of AoU's racial and ethnic diversity is unknown.nnOBJECTIVE: To quantify representation of key racial and ethnic groups in the accruing AoU nationwide health cohort and compare with their actual representation in the US.nnDESIGN, SETTING, AND PARTICIPANTS: This cohort study compared the AoU program from May 2017 to June 2022 for individuals 18 years and older with the Decennial Survey 2020 (DEC) collected by the US Census Bureau.nnEXPOSURES: Representation of non-Hispanic Asian, non-Hispanic Black or African American, Hispanic or Latino, non-Hispanic White, and uncategorized or multiple races in AoU.nnMAIN OUTCOMES AND MEASURES: The extent of underrepresentation or overrepresentation of each racial group in the AoU program at both nationwide and state-level relative to DEC.nnRESULTS: Of the 358 705 US adults in the AoU to date, individuals identified with the following race and ethnicity categories: 12 710 non-Hispanic Asian (3.5%), 73 348 non-Hispanic Black or African American (20.5%), 58 488 Hispanic or Latino (16.3%), 205 457 non-Hispanic White (57.3%), and 8702 uncategorized or reporting multiple categories (2.4%). Of 355 413 participants with available sex at birth and age data, 218 981 (61.6%) were female and had a mean (SD) age of 53.1 (17.0) years, 136 037 (38.28%) were male and had a mean (SD) age of 56.7 (17.0) years, and 395 reported nonbinary sex (0.1%), with a mean (SD) age of 55.4 (15.8) years. Compared with the referent US, non-Hispanic Black or African American individuals were overrepresented in the AoU by 8.73% (AoU, 20.5% [73 348 of 358 705] vs DEC, 11.7% [30 266 080 of 258 343 281]) and by relative scale, 1.94-fold. Non-Hispanic White individuals accounted for the greatest participation in the AoU with generally consistent dominance across all regions yet numerically underrepresented by absolute difference of -3.54% (95% CI, -3.70 to -3.38). Uncategorized or multiracial group in the AoU (2.4% [8702 of 358 705]) was 0.43-fold likely to be represented relative to the DEC (4.6% [11 922 096 of 258 343 281]) with an absolute difference of -2.19% (95% CI, -2.24 to -2.14). Moreover, non-Hispanic Asian individuals were underrepresented by -2.54% (95% CI, -2.60 to -2.48) prominently in most states. Individuals identifying as Hispanic or Latino were nominally underrepresented by -0.46% (95% CI, -0.58 to -0.34) (AoU, 16.3% [58 488 of 358 705] vs DEC, 16.8% [43 322 792 of 258 343 281]).nnCONCLUSIONS AND RELEVANCE: Recruitment trends for the ongoing AoU show relatively improved representation of some major race groups with geographic trends. These findings underscore the need to further tailor and augment recruitment and participation initiatives for diverse populations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37350734,
title = {Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study},
author = {So Mi Jemma Cho and Satoshi Koyama and Michael C Honigberg and Ida Surakka and Sara Haidermota and Shriienidhie Ganesh and Aniruddh P Patel and Romit Bhattacharya and Hokyou Lee and Hyeon Chang Kim and Pradeep Natarajan},
doi = {10.1093/eurheartj/ehad380},
issn = {1522-9645},
year  = {2023},
date = {2023-09-01},
journal = {Eur Heart J},
volume = {44},
number = {36},
pages = {3456--3465},
abstract = {AIMS: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence.nnMETHODS AND RESULTS: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD (0.74, 0.67-0.82). Additionally, age at enrolment, CAD PRS, C-reactive protein, lipoprotein(a), glucose, low-density lipoprotein cholesterol, deprivation, sleep quality, eGFR, and high-density lipoprotein (HDL) cholesterol also significantly associated with recurrence risk. Based on C indices (95% CI), the strongest predictors were CAD PRS (0.58, 0.57-0.59), HDL cholesterol (0.57, 0.57-0.58), and age at initial CAD event (0.57, 0.56-0.57). In addition to traditional risk factors, a comprehensive model improved the C index from 0.644 (0.632-0.654) to 0.676 (0.667-0.686).nnCONCLUSION: Sociodemographic, clinical, and laboratory factors are each associated with CAD recurrence with genetic risk, age at first CAD event, and HDL cholesterol concentration explaining the most.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37604963,
title = {GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data},
author = {Mehrtash Babadi and Jack M Fu and Samuel K Lee and Andrey N Smirnov and Laura D Gauthier and Mark Walker and David I Benjamin and Xuefang Zhao and Konrad J Karczewski and Isaac Wong and Ryan L Collins and Alba Sanchis-Juan and Harrison Brand and Eric Banks and Michael E Talkowski},
doi = {10.1038/s41588-023-01449-0},
issn = {1546-1718},
year  = {2023},
date = {2023-09-01},
journal = {Nat Genet},
volume = {55},
number = {9},
pages = {1589--1597},
abstract = {Copy number variants (CNVs) are major contributors to genetic diversity and disease. While standardized methods, such as the genome analysis toolkit (GATK), exist for detecting short variants, technical challenges have confounded uniform large-scale CNV analyses from whole-exome sequencing (WES) data. Given the profound impact of rare and de novo coding CNVs on genome organization and human disease, we developed GATK-gCNV, a flexible algorithm to discover rare CNVs from sequencing read-depth information, complete with open-source distribution via GATK. We benchmarked GATK-gCNV in 7,962 exomes from individuals in quartet families with matched genome sequencing and microarray data, finding up to 95% recall of rare coding CNVs at a resolution of more than two exons. We used GATK-gCNV to generate a reference catalog of rare coding CNVs in WES data from 197,306 individuals in the UK Biobank, and observed strong correlations between per-gene CNV rates and measures of mutational constraint, as well as rare CNV associations with multiple traits. In summary, GATK-gCNV is a tunable approach for sensitive and specific CNV discovery in WES data, with broad applications.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37732233,
title = {Characterizing the phenotypic and genetic structure of psychopathology in UK Biobank},
author = {Camille M Williams and Hugo Peyre and Tobias Wolfram and Younga H Lee and Tian Ge and Jordan W Smoller and Travis T Mallard and Franck Ramus},
doi = {10.1101/2023.09.05.23295086},
year  = {2023},
date = {2023-09-01},
journal = {medRxiv},
abstract = {Mental conditions exhibit a higher-order transdiagnostic factor structure which helps to explain the widespread comorbidity observed in psychopathology. However, the phenotypic and genetic structures of psychopathology may differ, raising questions about the validity and utility of these factors. Here, we study the phenotypic and genetic factor structures of ten psychiatric conditions using UK Biobank and public genomic data. Although the factor structure of psychopathology was generally genetically and phenotypically consistent, conditions related to externalizing (e.g., alcohol use disorder) and compulsivity (e.g., eating disorders) exhibited cross-level disparities in their relationships with other conditions, plausibly due to environmental influences. Domain-level factors, especially thought disorder and internalizing factors, were more informative than a general psychopathology factor in genome-wide association and polygenic index analyses. Collectively, our findings enhance the understanding of comorbidity and shared etiology, highlight the intricate interplay between genes and environment, and offer guidance for psychiatric research using polygenic indices.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37658615,
title = {Susceptibility gene profiling elucidates the pathogenesis of inflammatory bowel disease and provides precision medicine},
author = {Han Gao and Ruize Liu and Hailiang Huang and Zhanju Liu},
doi = {10.1002/ctm2.1404},
issn = {2001-1326},
year  = {2023},
date = {2023-09-01},
journal = {Clin Transl Med},
volume = {13},
number = {9},
pages = {e1404},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37755324,
title = {Community exposure to armed conflict and subsequent onset of alcohol use disorder},
author = {Ronny Bruffaerts and William G Axinn and Dirgha J Ghimire and Corina Benjet and Stephanie Chardoul and Kate M Scott and Ronald C Kessler and Paul Schulz and Jordan W Smoller},
doi = {10.1111/add.16343},
issn = {1360-0443},
year  = {2023},
date = {2023-09-01},
journal = {Addiction},
abstract = {AIMS: To measure the independent consequences of community-level armed conflict beatings on alcohol use disorders (AUD) among males in Nepal during and after the 2000-2006 conflict.nnDESIGN: A population-representative panel study from Nepal, with precise measures of community-level violent events and subsequent individual-level AUD in males. Females were not included because of low AUD prevalence.nnSETTING: Chitwan, Nepal.nnPARTICIPANTS: Four thousand eight hundred seventy-six males from 151 neighborhoods, systematically selected and representative of Western Chitwan. All residents aged 15-59 were eligible (response rate 93%).nnMEASUREMENTS: Measures of beatings in the community during the conflict (2000-2006), including the date and distance away, were gathered through neighborhood reports, geo-location and official resources, then linked to respondents' life histories of AUD (collected in 2016-2018) using the Nepal-specific Composite International Diagnostic Interview with life history calendar. Beatings nearby predict the subsequent onset of AUD during and after the armed conflict. Data were analyzed in 2021-2022.nnFINDINGS: Cohort-specific, discrete-time models revealed that within the youngest cohort (born 1992-2001), those living in neighborhoods where armed conflict beatings occurred were more likely to develop AUD compared with those in other neighborhoods (odds ratio = 1.66; 95% confidence interval = 1.02-2.71). In this cohort, a multilevel matching analysis designed to simulate a randomized trial showed the post-conflict incidence of AUD for those living in neighborhoods with any armed conflict beatings was 9.5% compared with 5.3% in the matched sample with no beatings.nnCONCLUSIONS: Among male children living in Chitwan, Nepal during the 2000-2006 armed conflict, living in a neighborhood where armed conflict beatings occurred is associated with increased odds of developing subsequent alcohol use disorder. This association was independent of personal exposure to beatings and other mental disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37732181,
title = {Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis},
author = {Md Mesbah Uddin and Seyedmohammad Saadatagah and Abhishek Niroula and Bing Yu and Whitney Hornsby and Shriienidhie Ganesh and Kim Lannery and Art Shuermans and Michael C Honigberg and Alexander G Bick and Peter Libby and Benjamin L Ebert and Christie M Ballantyne and Pradeep Natarajan},
doi = {10.1101/2023.09.05.23295093},
year  = {2023},
date = {2023-09-01},
journal = {medRxiv},
abstract = {Clonal hematopoiesis (CH), characterized by blood cells predominantly originating from a single mutated hematopoietic stem cell, is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CH is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CH. We found that age at baseline, sex, and dyslipidemia significantly influence the incidence of CH, while ASCVD and other traditional risk factors for ASCVD did not exhibit such associations. Our study also revealed associations between germline genetic variants and incident CH, prioritizing genes in CH development. Our comprehensive longitudinal assessment yields novel insights into the factors contributing to incident CH in older adults.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37679419,
title = {GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification},
author = {Vasiliki Lagou and Longda Jiang and Anna Ulrich and Liudmila Zudina and Karla Sofia Gutiérrez González and Zhanna Balkhiyarova and Alessia Faggian and Jared G Maina and Shiqian Chen and Petar V Todorov and Sodbo Sharapov and Alessia David and Letizia Marullo and Reedik Mägi and Roxana-Maria Rujan and Emma Ahlqvist and Gudmar Thorleifsson and Ηe Gao and Εvangelos Εvangelou and Beben Benyamin and Robert A Scott and Aaron Isaacs and Jing Hua Zhao and Sara M Willems and Toby Johnson and Christian Gieger and Harald Grallert and Christa Meisinger and Martina Müller-Nurasyid and Rona J Strawbridge and Anuj Goel and Denis Rybin and Eva Albrecht and Anne U Jackson and Heather M Stringham and Ivan R Corrêa and Eric Farber-Eger and Valgerdur Steinthorsdottir and André G Uitterlinden and Patricia B Munroe and Morris J Brown and Julian Schmidberger and Oddgeir Holmen and Barbara Thorand and Kristian Hveem and Tom Wilsgaard and Karen L Mohlke and Zhe Wang and  and Aleksey Shmeliov and Marcel den Hoed and Ruth J F Loos and Wolfgang Kratzer and Mark Haenle and Wolfgang Koenig and Bernhard O Boehm and Tricia M Tan and Alejandra Tomas and Victoria Salem and Inês Barroso and Jaakko Tuomilehto and Michael Boehnke and Jose C Florez and Anders Hamsten and Hugh Watkins and Inger Njølstad and H-Erich Wichmann and Mark J Caulfield and Kay-Tee Khaw and Cornelia M van Duijn and Albert Hofman and Nicholas J Wareham and Claudia Langenberg and John B Whitfield and Nicholas G Martin and Grant Montgomery and Chiara Scapoli and Ioanna Tzoulaki and Paul Elliott and Unnur Thorsteinsdottir and Kari Stefansson and Evan L Brittain and Mark I McCarthy and Philippe Froguel and Patrick M Sexton and Denise Wootten and Leif Groop and Josée Dupuis and James B Meigs and Giuseppe Deganutti and Ayse Demirkan and Tune H Pers and Christopher A Reynolds and Yurii S Aulchenko and Marika A Kaakinen and Ben Jones and Inga Prokopenko and },
doi = {10.1038/s41588-023-01462-3},
issn = {1546-1718},
year  = {2023},
date = {2023-09-01},
journal = {Nat Genet},
volume = {55},
number = {9},
pages = {1448--1461},
abstract = {Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37463579,
title = {Phenotype and genetic analysis of data collected within the first year of NeuroDev},
author = {Patricia Kipkemoi and Heesu Ally Kim and Bjorn Christ and Emily O'Heir and Jake Allen and Christina Austin-Tse and Samantha Baxter and Harrison Brand and Sam Bryant and Nick Buser and Victoria de Menil and Emma Eastman and Serini Murugasen and Alice Galvin and Martha Kombe and Alfred Ngombo and Beatrice Mkubwa and Paul Mwangi and Collins Kipkoech and Alysia Lovgren and Daniel G MacArthur and Brigitte Melly and Katini Mwangasha and Alicia Martin and Lethukuthula L Nkambule and Alba Sanchis-Juan and Moriel Singer-Berk and Michael E Talkowski and Grace VanNoy and Celia van der Merwe and  and Charles Newton and Anne O'Donnell-Luria and Amina Abubakar and Kirsten A Donald and Elise B Robinson},
doi = {10.1016/j.neuron.2023.06.010},
issn = {1097-4199},
year  = {2023},
date = {2023-09-01},
journal = {Neuron},
volume = {111},
number = {18},
pages = {2800--2810.e5},
abstract = {Genetic association studies have made significant contributions to our understanding of the etiology of neurodevelopmental disorders (NDDs). However, these studies rarely focused on the African continent. The NeuroDev Project aims to address this diversity gap through detailed phenotypic and genetic characterization of children with NDDs from Kenya and South Africa. We present results from NeuroDev's first year of data collection, including phenotype data from 206 cases and clinical genetic analyses of 99 parent-child trios. Most cases met criteria for global developmental delay/intellectual disability (GDD/ID, 80.3%). Approximately half of the children with GDD/ID also met criteria for autism. Analysis of exome-sequencing data identified a pathogenic or likely pathogenic variant in 13 (17%) of the 75 cases from South Africa and 9 (38%) of the 24 cases from Kenya. Data from the trio pilot are publicly available, and the NeuroDev Project will continue to develop resources for the global genetics community.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37384397,
title = {Multi-ancestry genome-wide analysis identifies shared genetic effects and common genetic variants for self-reported sleep duration},
author = {B H Scammell and C Tchio and Y Song and T Nishiyama and T L Louie and H S Dashti and M Nakatochi and P C Zee and I Daghlas and Y Momozawa and J Cai and H M Ollila and S Redline and K Wakai and T Sofer and S Suzuki and J M Lane and R Saxena},
doi = {10.1093/hmg/ddad101},
issn = {1460-2083},
year  = {2023},
date = {2023-09-01},
journal = {Hum Mol Genet},
volume = {32},
number = {18},
pages = {2797--2807},
abstract = {Both short (≤6 h per night) and long sleep duration (≥9 h per night) are associated with increased risk of chronic diseases. Despite evidence linking habitual sleep duration and risk of disease, the genetic determinants of sleep duration in the general population are poorly understood, especially outside of European (EUR) populations. Here, we report that a polygenic score of 78 European ancestry sleep duration single-nucleotide polymorphisms (SNPs) is associated with sleep duration in an African (n = 7288; P = 0.003), an East Asian (n = 13 618; P = 6 × 10-4) and a South Asian (n = 7485; P = 0.025) genetic ancestry cohort, but not in a Hispanic/Latino cohort (n = 8726; P = 0.71). Furthermore, in a pan-ancestry (N = 483 235) meta-analysis of genome-wide association studies (GWAS) for habitual sleep duration, 73 loci are associated with genome-wide statistical significance. Follow-up of five loci (near HACD2, COG5, PRR12, SH3RF1 and KCNQ5) identified expression-quantitative trait loci for PRR12 and COG5 in brain tissues and pleiotropic associations with cardiovascular and neuropsychiatric traits. Overall, our results suggest that the genetic basis of sleep duration is at least partially shared across diverse ancestry groups.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37721944,
title = {eQTL Catalogue 2023: New datasets, X chromosome QTLs, and improved detection and visualisation of transcript-level QTLs},
author = {Nurlan Kerimov and Ralf Tambets and James D Hayhurst and Ida Rahu and Peep Kolberg and Uku Raudvere and Ivan Kuzmin and Anshika Chowdhary and Andreas Vija and Hans J Teras and Masahiro Kanai and Jacob Ulirsch and Mina Ryten and John Hardy and Sebastian Guelfi and Daniah Trabzuni and Sarah Kim-Hellmuth and William Rayner and Hilary Finucane and Hedi Peterson and Abayomi Mosaku and Helen Parkinson and Kaur Alasoo},
doi = {10.1371/journal.pgen.1010932},
issn = {1553-7404},
year  = {2023},
date = {2023-09-01},
journal = {PLoS Genet},
volume = {19},
number = {9},
pages = {e1010932},
abstract = {The eQTL Catalogue is an open database of uniformly processed human molecular quantitative trait loci (QTLs). We are continuously updating the resource to further increase its utility for interpreting genetic associations with complex traits. Over the past two years, we have increased the number of uniformly processed studies from 21 to 31 and added X chromosome QTLs for 19 compatible studies. We have also implemented Leafcutter to directly identify splice-junction usage QTLs in all RNA sequencing datasets. Finally, to improve the interpretability of transcript-level QTLs, we have developed static QTL coverage plots that visualise the association between the genotype and average RNA sequencing read coverage in the region for all 1.7 million fine mapped associations. To illustrate the utility of these updates to the eQTL Catalogue, we performed colocalisation analysis between vitamin D levels in the UK Biobank and all molecular QTLs in the eQTL Catalogue. Although most GWAS loci colocalised both with eQTLs and transcript-level QTLs, we found that visual inspection could sometimes be used to distinguish primary splicing QTLs from those that appear to be secondary consequences of large-effect gene expression QTLs. While these visually confirmed primary splicing QTLs explain just 6/53 of the colocalising signals, they are significantly less pleiotropic than eQTLs and identify a prioritised causal gene in 4/6 cases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37740458,
title = {Sustainability of personal social networks of people with Down syndrome},
author = {Ayesha Harisinghani and Amar Dhand and Ellen Hollands Steffensen and Brian G Skotko},
doi = {10.1002/ajmg.c.32064},
issn = {1552-4876},
year  = {2023},
date = {2023-09-01},
journal = {Am J Med Genet C Semin Med Genet},
pages = {e32064},
abstract = {Research continues to demonstrate that the characteristics of one's social network could have an impact on the development of Alzheimer's disease. Given the predisposition of people with Down syndrome to develop Alzheimer's disease, analysis of their social networks has become an emerging focus. Previous pilot research demonstrated that the personal networks of people with DS could be quantitatively analyzed, with no difference between self-report and parent-proxy report. This manuscript focuses on a 12-month follow-up period with the same original participants (24 adults with Down syndrome). Their social networks demonstrated sustainability, but not improvement, as reported by people with DS (mean network size: 8.88; mean density: 0.73; mean constraint: 0.44; mean effective size: 3.58; mean max degree: 6.04; mean degree: 4.78) and their proxies (mean network size: 7.90; mean density: 0.82; mean constraint: 53.13; mean effective size: 2.87; mean max degree: 5.19; mean degree: 4.30). Intentional and continued efforts are likely needed in order to improve the social network measures of people with Down syndrome.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37598461,
title = {Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma},
author = {Kathryn Recto and Priyadarshini Kachroo and Tianxiao Huan and David Van Den Berg and Gha Young Lee and Helena Bui and Dong Heon Lee and Jessica Gereige and Chen Yao and Shih-Jen Hwang and Roby Joehanes and Scott T Weiss and  and George T O'Connor and Daniel Levy and Dawn L DeMeo},
doi = {10.1016/j.ebiom.2023.104758},
issn = {2352-3964},
year  = {2023},
date = {2023-09-01},
journal = {EBioMedicine},
volume = {95},
pages = {104758},
abstract = {BACKGROUND: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases.nnMETHODS: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables.nnFINDINGS: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P < 7.94E-04) that can be explored as potential therapeutic targets.nnINTERPRETATION: By integrating eQTM and MR analyses in general and clinical asthma populations, our findings provide a deeper understanding of the multidimensional inter-relations of DNA methylation, gene expression, and IgE levels.nnFUNDING: US NIH/NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37582372,
title = {Prioritization of therapeutic targets for dyslipidemia using integrative multi-omics and multi-trait analysis},
author = {Min Seo Kim and Minku Song and Beomsu Kim and Injeong Shim and Dan Say Kim and Pradeep Natarajan and Ron Do and Hong-Hee Won},
doi = {10.1016/j.xcrm.2023.101112},
issn = {2666-3791},
year  = {2023},
date = {2023-09-01},
journal = {Cell Rep Med},
volume = {4},
number = {9},
pages = {101112},
abstract = {Drug targets with genetic support are several-fold more likely to succeed in clinical trials. We introduce a genetic-driven approach based on causal inferences that can inform drug target prioritization, repurposing, and adverse effects of using lipid-lowering agents. Given that a multi-trait approach increases the power to detect meaningful variants/genes, we conduct multi-omics and multi-trait analyses, followed by network connectivity investigations, and prioritize 30 potential therapeutic targets for dyslipidemia, including SORT1, PSRC1, CELSR2, PCSK9, HMGCR, APOB, GRN, HFE2, FJX1, C1QTNF1, and SLC5A8. 20% (6/30) of prioritized targets from our hypothesis-free drug target search are either approved or under investigation for dyslipidemia. The prioritized targets are 22-fold higher in likelihood of being approved or under investigation in clinical trials than genome-wide association study (GWAS)-curated targets. Our results demonstrate that the genetic-driven approach used in this study is a promising strategy for prioritizing targets while informing about the potential adverse effects and repurposing opportunities.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37719151,
title = {Aligning NIH's existing data use restrictions to the GA4GH DUO standard},
author = {Jonathan Lawson and Elena M Ghanaim and Jinyoung Baek and Harin Lee and Heidi L Rehm},
doi = {10.1016/j.xgen.2023.100381},
issn = {2666-979X},
year  = {2023},
date = {2023-09-01},
journal = {Cell Genom},
volume = {3},
number = {9},
pages = {100381},
abstract = {It is widely accepted that large-scale genomic data (e.g., whole-genome sequencing, whole-exome sequencing, and genome-wide association study data) be shared through a controlled-access mechanism. This protects the privacy of research participants and ensures downstream uses of data align with participants' informed consent regarding future sharing of their data. In 2019, GA4GH approved the Data Use Ontology (DUO) standard to define data use terms with machine-readable representations to represent how a dataset can be used. We endeavored to determine the parity of existing data use restrictions ("Data Use Limitations" [DULs]) for datasets registered in the National Institutes of Health database for Genotypes and Phenotypes (dbGaP) with the DUO standard. We found substantial (93%) parity between the dbGaP DULs (n = 3,575) and DUO. This study demonstrates the comprehensiveness of the DUO standard and encourages data stewards to standardize data use restrictions in machine-readable formats to facilitate data sharing.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37481209,
title = {Lipoylation is dependent on the ferredoxin FDX1 and dispensable under hypoxia in human cells},
author = {Pallavi R Joshi and Shayan Sadre and Xiaoyan A Guo and Jason G McCoy and Vamsi K Mootha},
doi = {10.1016/j.jbc.2023.105075},
issn = {1083-351X},
year  = {2023},
date = {2023-09-01},
journal = {J Biol Chem},
volume = {299},
number = {9},
pages = {105075},
abstract = {Iron-sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environmental sensing, and catalysis. Amongst the most ancient ISC-containing proteins are the ferredoxin (FDX) family of electron carriers. Humans have two FDXs- FDX1 and FDX2, both of which are localized to mitochondria, and the latter of which is itself important for ISC synthesis. We have previously shown that hypoxia can eliminate the requirement for some components of the ISC biosynthetic pathway, but FDXs were not included in that study. Here, we report that FDX1, but not FDX2, is dispensable under 1% O in cultured human cells. We find that FDX1 is essential for production of the lipoic acid cofactor, which is synthesized by the ISC-containing enzyme lipoyl synthase. While hypoxia can rescue the growth phenotype of either FDX1 or lipoyl synthase KO cells, lipoylation in these same cells is not rescued, arguing against an alternative biosynthetic route or salvage pathway for lipoate in hypoxia. Our work reveals the divergent roles of FDX1 and FDX2 in mitochondria, identifies a role for FDX1 in lipoate synthesis, and suggests that loss of lipoic acid can be tolerated under low oxygen tensions in cell culture.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37701331,
title = {Classical phenylketonuria presenting as maternal PKU syndrome in the offspring of an intellectually normal woman},
author = {Malak Ali Alghamdi and Anne O'Donnell-Luria and Naif A Almontashiri and Wajeih Y AlAali and Hebatallah H Ali and Harvey L Levy},
doi = {10.1002/jmd2.12384},
issn = {2192-8304},
year  = {2023},
date = {2023-09-01},
journal = {JIMD Rep},
volume = {64},
number = {5},
pages = {312--316},
abstract = {Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH). If untreated by dietary restriction of phenylalanine intake, impaired postnatal cognitive development results from the neurotoxic effects of excessive phenylalanine (Phe). Signs and symptoms include severe intellectual disability and behavior problems with a high frequency of seizures and variable microcephaly. Maternal PKU syndrome refers to fetal damage resulting in congenital abnormalities when the mother has untreated PKU during pregnancy. Here, we report an intellectually normal 32-year-old female who presented with recurrent pregnancy loss and two neonatal deaths with congenital heart disease, microcephaly, intrauterine growth restriction, and respiratory distress. She was diagnosed with PKU through exome sequencing performed for carrier testing with a homozygous pathogenic variant in the PAH gene, c.169_171del, p.(Glu57del) that is associated with classical PKU. Consistent with the genetic finding, she had a markedly increased plasma phenylalanine concentration of 1642 μmol/L (normal <100). This case demonstrates that recurrent pregnancy loss due to untreated maternal PKU may present as an initial finding in otherwise unsuspected classical PKU and illustrates that extreme degrees of variable expressivity may occur in classical PKU. Moreover, this case illustrates the value of genomic sequencing of women who experience recurrent pregnancy loss or neonatal anomalies.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37697398,
title = {Use of electronic health record data mining for heart failure subtyping},
author = {Matti A Vuori and Tuomo Kiiskinen and Niina Pitkänen and Samu Kurki and Hannele Laivuori and Tarja Laitinen and Sampo Mäntylahti and Aarno Palotie and FinnGen and Teemu J Niiranen},
doi = {10.1186/s13104-023-06469-x},
issn = {1756-0500},
year  = {2023},
date = {2023-09-01},
journal = {BMC Res Notes},
volume = {16},
number = {1},
pages = {208},
abstract = {OBJECTIVE: To assess whether electronic health record (EHR) data text mining can be used to improve register-based heart failure (HF) subtyping. EHR data of 43,405 individuals from two Finnish hospital biobanks were mined for unstructured text mentions of ejection fraction (EF) and validated against clinical assessment in two sets of 100 randomly selected individuals. Structured laboratory data was then incorporated for a categorization by HF subtype (HF with mildly reduced EF, HFmrEF; HF with preserved EF, HFpEF; HF with reduced EF, HFrEF; and no HF).nnRESULTS: In 86% of the cases, the algorithm-identified EF belonged to the correct HF subtype range. Sensitivity, specificity, PPV and NPV of the algorithm were 94-100% for HFrEF, 85-100% for HFmrEF, and 96%, 67%, 53% and 98% for HFpEF. Survival analyses using the traditional diagnosis of HF were in concordance with the algorithm-based ones. Compared to healthy individuals, mortality increased from HFmrEF (hazard ratio [HR], 1.91; 95% confidence interval [CI], 1.24-2.95) to HFpEF (2.28; 1.80-2.88) to HFrEF group (2.63; 1.97-3.50) over a follow-up of 1.5 years. We conclude that quantitative EF data can be efficiently extracted from EHRs and used with laboratory data to subtype HF with reasonable accuracy, especially for HFrEF.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37498674,
title = {Genetic modification of inflammation- and clonal hematopoiesis-associated cardiovascular risk},
author = {Zhi Yu and Trevor P Fidler and Yunfeng Ruan and Caitlyn Vlasschaert and Tetsushi Nakao and Md Mesbah Uddin and Taralynn Mack and Abhishek Niroula and J Brett Heimlich and Seyedeh M Zekavat and Christopher J Gibson and Gabriel K Griffin and Yuxuan Wang and Gina M Peloso and Nancy Heard-Costa and Daniel Levy and Ramachandran S Vasan and François Aguet and Kristin G Ardlie and Kent D Taylor and Stephen S Rich and Jerome I Rotter and Peter Libby and Siddhartha Jaiswal and Benjamin L Ebert and Alexander G Bick and Alan R Tall and Pradeep Natarajan},
doi = {10.1172/JCI168597},
issn = {1558-8238},
year  = {2023},
date = {2023-09-01},
journal = {J Clin Invest},
volume = {133},
number = {18},
abstract = {Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risk. We show that CRISPR-induced Asxl1-mutated murine macrophages had a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVD-protective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides evidence to support gene-specific strategies to address CHIP-associated CVD risk.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37653029,
title = {GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture},
author = { },
doi = {10.1038/s41588-023-01485-w},
issn = {1546-1718},
year  = {2023},
date = {2023-09-01},
journal = {Nat Genet},
volume = {55},
number = {9},
pages = {1471--1482},
abstract = {Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37191094,
title = {Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy},
author = {Vandana Shashi and Kelly Schoch and Rebecca Ganetzky and Peter G Kranz and Neal Sondheimer and M Louise Markert and Heidi Cope and Azita Sadeghpour and Philip Roehrs and Thomas Arbogast and Colleen Muraresku and  and Amanda V Tyndall and Michael J Esser and Kristine E Woodward and Billie Ping-Yee Au and Jillian S Parboosingh and Ryan E Lamont and Francois P Bernier and Nicola A M Wright and Susa M Benseler and Simon J Parsons and Mays El-Dairi and Edward C Smith and Purnima Valdez and Michael Tennison and A Micheil Innes and Erica E Davis},
doi = {10.1016/j.gim.2023.100897},
issn = {1530-0366},
year  = {2023},
date = {2023-09-01},
journal = {Genet Med},
volume = {25},
number = {9},
pages = {100897},
abstract = {PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype.nnMETHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy.nnRESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family.nnCONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37034728,
title = {Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes},
author = {Sylvanus Toikumo and Mariela V Jennings and Benjamin K Pham and Hyunjoon Lee and Travis T Mallard and Sevim B Bianchi and John J Meredith and Laura Vilar-Ribó and Heng Xu and Alexander S Hatoum and Emma C Johnson and Vanessa Pazdernik and Zeal Jinwala and Shreya R Pakala and Brittany S Leger and Maria Niarchou and Michael Ehinmowo and  and  and Greg D Jenkins and Anthony Batzler and Richard Pendegraft and Abraham A Palmer and Hang Zhou and Joanna M Biernacka and Brandon J Coombes and Joel Gelernter and Ke Xu and Dana B Hancock and Cox J Nancy and Jordan W Smoller and Lea K Davis and Amy C Justice and Henry R Kranzler and Rachel L Kember and Sandra Sanchez-Roige},
doi = {10.1101/2023.03.27.23287713},
year  = {2023},
date = {2023-09-01},
journal = {medRxiv},
abstract = {Tobacco use disorder (  ) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies (  ) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records,  ) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37683329,
title = {Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy},
author = {Isabelle Weinhofer and Paulus Rommer and Andreas Gleiss and Markus Ponleitner and Bettina Zierfuss and Petra Waidhofer-Söllner and Stéphane Fourcade and Katharina Grabmeier-Pfistershammer and Marie-Christine Reinert and Jens Göpfert and Anne Heine and Hemmo A F Yska and Carlos Casasnovas and Verónica Cantarín and Caroline G Bergner and Eric Mallack and Sonja Forss-Petter and Patrick Aubourg and Annette Bley and Marc Engelen and Florian Eichler and Troy C Lund and Aurora Pujol and Wolfgang Köhler and Jörn-Sven Kühl and Johannes Berger},
doi = {10.1016/j.ebiom.2023.104781},
issn = {2352-3964},
year  = {2023},
date = {2023-09-01},
journal = {EBioMedicine},
volume = {96},
pages = {104781},
abstract = {BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is highly variable, ranging from slowly progressive adrenomyeloneuropathy to severe brain demyelination and inflammation (cerebral ALD, CALD) affecting males with childhood peak onset. Risk models integrating blood-based biomarkers to indicate CALD onset, enabling timely interventions, are lacking. Therefore, we evaluated the prognostic value of blood biomarkers in addition to current neuroimaging predictors for early detection of CALD.nnMETHODS: We measured blood biomarkers in a retrospective, male CALD risk-assessment cohort consisting of 134 X-ALD patients and 66 controls and in a phenotype-blinded validation set (25 X-ALD boys, 4-13 years) using Simoa®and Luminex® technologies.nnFINDINGS: Among 25 biomarkers indicating axonal damage, astrocye/microglia activation, or immune-cell recruitment, neurofilament light chain (NfL) had the highest prognostic value for early indication of childhood/adolescent CALD. A plasma NfL cut-off level of 8.33 pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96% [95% CI: 80-100] in the validation group. Multivariable logistic regression models revealed that combining NfL with GFAP or cytokines/chemokines (IL-15, IL-12p40, CXCL8, CCL11, CCL22, and IL-4) that were significantly elevated in CALD vs healthy controls had no additional benefit for detecting neuroinflammation. Some cytokines/chemokines were elevated only in childhood/adolescent CALD and already upregulated in asymptomatic X-ALD children (IL-15, IL-12p40, and CCL7). In adults, NfL levels distinguished CALD but were lower than in childhood/adolescent CALD patients with similar (MRI) lesion severity. Blood GFAP did not differentiate CALD from non-inflammatory X-ALD.nnINTERPRETATION: Biomarker-based risk prediction with a plasma NfL cut-off value of 8.33 pg/mL, determined by ROC analysis, indicates CALD onset with high sensitivity and specificity in childhood X-ALD patients. A specific pro-inflammatory cytokine/chemokine profile in asymptomatic X-ALD boys may indicate a primed, immanent inflammatory state aligning with peak onset of CALD. Age-related differences in biomarker levels in adult vs childhood CALD patients warrants caution in predicting onset and progression of CALD in adults. Further evaluations are needed to assess clinical utility of the NfL cut-off for risk prognosis of CALD onset.nnFUNDING: Austrian Science Fund, European Leukodystrophy Association.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37790445,
title = {Genetic Sex Validation for Sample Tracking in Clinical Testing},
author = {Jianhong Hu and Viktoriya Korchina and Hana Zouk and Maegan V Harden and David Murdock and Alyssa Macbeth and Steven M Harrison and Niall Lennon and Christie Kovar and Adithya Balasubramanian and Lan Zhang and Gauthami Chandanavelli and Divya Pasham and Robb Rowley and Ken Wiley and Maureen E Smith and Adam Gordon and Gail P Jarvik and Patrick Sleiman and Melissa A Kelly and Harris T Bland and Mullai Murugan and Eric Venner and Eric Boerwinkle and Cynthia Prows and Lisa Mahanta and Heidi L Rehm and Richard A Gibbs and Donna M Muzny},
doi = {10.21203/rs.3.rs-3304685/v1},
year  = {2023},
date = {2023-09-01},
journal = {Res Sq},
abstract = {Objective Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups. Results Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors, samples from transgender participants and stem cell or bone marrow transplant patients along with undetermined sample mix-ups.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37769026,
title = {CIRCUST: A novel methodology for temporal order reconstruction of molecular rhythms; validation and application towards a daily rhythm gene expression atlas in humans},
author = {Yolanda Larriba and Ivy C Mason and Richa Saxena and Frank A J L Scheer and Cristina Rueda},
doi = {10.1371/journal.pcbi.1011510},
issn = {1553-7358},
year  = {2023},
date = {2023-09-01},
journal = {PLoS Comput Biol},
volume = {19},
number = {9},
pages = {e1011510},
abstract = {The circadian system drives near-24-h oscillations in behaviors and biological processes. The underlying core molecular clock regulates the expression of other genes, and it has been shown that the expression of more than 50 percent of genes in mammals displays 24-h rhythmic patterns, with the specific genes that cycle varying from one tissue to another. Determining rhythmic gene expression patterns in human tissues sampled as single timepoints has several challenges, including the reconstruction of temporal order of highly noisy data. Previous methodologies have attempted to address these challenges in one or a small number of tissues for which clock gene evolutionary conservation is assumed to be preserved. Here we introduce CIRCUST, a novel CIRCular-robUST methodology for analyzing molecular rhythms, that relies on circular statistics, is robust against noise, and requires fewer assumptions than existing methodologies. Next, we validated the method against four controlled experiments in which sampling times were known, and finally, CIRCUST was applied to 34 tissues from the Genotype-Tissue Expression (GTEx) dataset with the aim towards building a comprehensive daily rhythm gene expression atlas in humans. The validation and application shown here indicate that CIRCUST provides a flexible framework to formulate and solve the issues related to the analysis of molecular rhythms in human tissues. CIRCUST methodology is publicly available at https://github.com/yolandalago/CIRCUST/.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37694688,
title = {Genetically Predicted Gestational Age and Birth Weight Are Associated With Cardiac and Pulmonary Vascular Remodeling in Adulthood},
author = {Art Schuermans and Maddalena Ardissino and Victor Nauffal and Shaan Khurshid and James P Pirruccello and Patrick T Ellinor and Adam J Lewandowski and Pradeep Natarajan and Michael C Honigberg},
doi = {10.1093/eurjpc/zwad296},
issn = {2047-4881},
year  = {2023},
date = {2023-09-01},
journal = {Eur J Prev Cardiol},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37682406,
title = {Factorial validity and comparability of the six translations of the Rivermead Post-Concussion Symptoms Questionnaire translations: results from the CENTER-TBI study},
author = {Marina Zeldovich and Fabian Bockhop and Amra Covic and Isabelle Mueller and Suzanne Polinder and Ana Mikolic and Marjolein van der Vlegel and Nicole von Steinbuechel and },
doi = {10.1186/s41687-023-00632-5},
issn = {2509-8020},
year  = {2023},
date = {2023-09-01},
journal = {J Patient Rep Outcomes},
volume = {7},
number = {1},
pages = {90},
abstract = {BACKGROUND: Comparison of patient-reported outcomes in multilingual studies requires evidence of the equivalence of translated versions of the questionnaires. The present study examines the factorial validity and comparability of six language versions of the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) administered to individuals following traumatic brain injury (TBI) in the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) study.nnMETHODS: Six competing RPQ models were estimated using data from Dutch (n = 597), English (n = 223), Finnish (n = 213), Italian (n = 268), Norwegian (n = 263), and Spanish (n = 254) language samples recruited six months after injury. To determine whether the same latent construct was measured by the best-fitting model across languages and TBI severity groups (mild/moderate vs. severe), measurement invariance (MI) was tested using a confirmatory factor analysis framework.nnRESULTS: The results did not indicate a violation of the MI assumption. The six RPQ translations were largely comparable across languages and were able to capture the same construct across TBI severity groups. The three-factor solution comprising emotional, cognitive, and somatic factors provided the best fit with the following indices for the total sample: χ (101) = 647.04, [Formula: see text]= 6.41, p < 0.001, CFI = 0.995, TLI = 0.994, RMSEA = 0.055, CI[0.051, 0.059], SRMR = 0.051.nnCONCLUSION: The RPQ can be used in international research and clinical settings, allowing direct comparisons of scores across languages analyzed within the full spectrum of TBI severity. To strengthen the aggregated applicability across languages, further analyses of the utility of the response scale and comparisons between different translations of the RPQ at the item level are recommended.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37738616,
title = {Sleep regularity is a stronger predictor of mortality risk than sleep duration: A prospective cohort study},
author = {Daniel P Windred and Angus C Burns and Jacqueline M Lane and Richa Saxena and Martin K Rutter and Sean W Cain and Andrew J K Phillips},
doi = {10.1093/sleep/zsad253},
issn = {1550-9109},
year  = {2023},
date = {2023-09-01},
journal = {Sleep},
abstract = {Abnormally short and long sleep are associated with premature mortality, and achieving optimal sleep duration has been the focus for sleep health guidelines. Emerging research demonstrates that sleep regularity, the day-to-day consistency of sleep-wake timing, can be a stronger predictor for some health outcomes than sleep duration. The role of sleep regularity in mortality, however, has not been investigated in a large cohort with objective data. We therefore aimed to compare how sleep regularity and duration predicted risk for all-cause and cause-specific mortality. We calculated Sleep Regularity Index (SRI) scores from >10 million hours of accelerometer data in 60,977 UK Biobank participants (62.8±7.8 years, 55.0% female, median[IQR] SRI: 81.0[73.8-86.3]). Mortality was reported up to 7.8 years after accelerometer recording in 1,859 participants (4.84 deaths per 1000 person-years, mean (±SD) follow up of 6.30±0.83 years). Higher sleep regularity was associated with a 20-48% lower risk of all-cause mortality (p<.001 to p=0.004), a 16-39% lower risk of cancer mortality (p<0.001 to p=0.017), and a 22-57% lower risk of cardiometabolic mortality (p<0.001 to p=0.048), across the top four SRI quintiles compared to the least regular quintile. Results were adjusted for age, sex, ethnicity, and sociodemographic, lifestyle, and health factors. Sleep regularity was a stronger predictor of all-cause mortality than sleep duration, by comparing equivalent mortality models, and by comparing nested SRI-mortality models with and without sleep duration (p=0.14-0.20). These findings indicate that sleep regularity is an important predictor for mortality risk and is a stronger predictor than sleep duration. Sleep regularity may be a simple, effective target for improving general health and survival.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37790568,
title = {Heterogeneous effects on type 2 diabetes and cardiovascular outcomes of genetic variants and traits associated with fasting insulin},
author = {Alisa Manning and Magdalena Sevilla-González and Kirk Smith and Ningyuan Wang and Aubrey Jensen and Elizabeth Litkowski and Hyunkyung Kim and Daniel DiCorpo and Kenneth Westerman and Jinrui Cui and Ching-Ti Liu and Chenglong Yu and John McNeil and Paul Lacaze and Kyong-Mi Chang and Phil Tsao and Lawrence Phillips and Mark Goodarzi and Rob Sladek and Jerome Rotter and Josee Dupuis and Jose Florez and Jordi Merino and James Meigs and Jin Zhou and Sridharan Raghavan and Miriam Udler},
doi = {10.21203/rs.3.rs-3317661/v1},
year  = {2023},
date = {2023-09-01},
journal = {Res Sq},
abstract = {Hyperinsulinemia is a complex and heterogeneous phenotype that characterizes molecular alterations that precede the development of type 2 diabetes (T2D). It results from a complex combination of molecular processes, including insulin secretion and insulin sensitivity, that differ between individuals. To better understand the physiology of hyperinsulinemia and ultimately T2D, we implemented a genetic approach grouping fasting insulin (FI)-associated genetic variants based on their molecular and phenotypic similarities. We identified seven distinctive genetic clusters representing different physiologic mechanisms leading to rising FI levels, ranging from clusters of variants with effects on increased FI, but without increased risk of T2D (non-diabetogenic hyperinsulinemia), to clusters of variants that increase FI and T2D risk with demonstrated strong effects on body fat distribution, liver, lipid, and inflammatory processes (diabetogenic hyperinsulinemia). We generated cluster-specific polygenic scores in 1,104,258 individuals from five multi-ancestry cohorts to show that the clusters differed in associations with cardiometabolic traits. Among clusters characterized by non-diabetogenic hyperinsulinemia, there was both increased and decreased risk of coronary artery disease despite the non-increased risk of T2D. Similarly, the clusters characterized by diabetogenic hyperinsulinemia were associated with an increased risk of T2D, yet had differing risks of cardiovascular conditions, including coronary artery disease, myocardial infarction, and stroke. The strongest cluster-T2D associations were observed with the same direction of effect in non-Hispanic Black, Hispanic, non-Hispanic White, and non-Hispanic East Asian populations. These genetic clusters provide important insights into granular metabolic processes underlying the physiology of hyperinsulinemia, notably highlighting specific processes that decouple increasing FI levels from T2D and cardiovascular risk. Our findings suggest that increasing FI levels are not invariably associated with adverse cardiometabolic outcomes.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37730841,
title = {Brain microvascular endothelial cells and blood-brain barrier dysfunction in psychotic disorders},
author = {Paulo Lizano and Sovannarath Pong and Stephanie Santarriaga and Deepthi Bannai and Rakesh Karmacharya},
doi = {10.1038/s41380-023-02255-0},
issn = {1476-5578},
year  = {2023},
date = {2023-09-01},
journal = {Mol Psychiatry},
abstract = {Although there is convergent evidence for blood-brain barrier (BBB) dysfunction and peripheral inflammation in schizophrenia (SZ) and bipolar disorder (BD), it is unknown whether BBB deficits are intrinsic to brain microvascular endothelial cells (BMECs) or arise via effects of peripheral inflammatory cytokines. We examined BMEC function using stem cell-based models to identify cellular and molecular deficits associated with BBB dysfunction in SZ and BD. Induced pluripotent stem cells (iPSCs) from 4 SZ, 4 psychotic BD and 4 healthy control (HC) subjects were differentiated into BMEC-"like" cells. Gene expression and protein levels of tight junction proteins were assessed. Transendothelial electrical resistance (TEER) and permeability were assayed to evaluate BBB function. Cytokine levels were measured from conditioned media. BMECs derived from human iPSCs in SZ and BD did not show differences in BBB integrity or permeability compared to HC BMECs. Outlier analysis using TEER revealed a BBB-deficit (n = 3) and non-deficit (n = 5) group in SZ and BD lines. Stratification based on BBB function in SZ and BD patients identified a BBB-deficit subtype with reduced barrier function, tendency for increased permeability to smaller molecules, and decreased claudin-5 (CLDN5) levels. BMECs from the BBB-deficit group show increased matrix metallopeptidase 1 (MMP1) activity, which correlated with reduced CLDN5 and worse BBB function, and was improved by tumor necrosis factor α (TNFα) and MMP1 inhibition. These results show potential deficits in BMEC-like cells in psychotic disorders that result in BBB disruption and further identify TNFα and MMP1 as promising targets for ameliorating BBB deficits.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37745486,
title = {The genetic underpinnings of variable penetrance and expressivity of pathogenic mutations in cardiometabolic traits},
author = {Angela Wei and Richard Border and Boyang Fu and Sinéad Cullina and Nadav Brandes and Sriram Sankararaman and Eimear E Kenny and Miriam S Udler and Vasilis Ntranos and Noah Zaitlen and Valerie A Arboleda},
doi = {10.1101/2023.09.14.23295564},
year  = {2023},
date = {2023-09-01},
journal = {medRxiv},
abstract = {Over three percent of people carry a dominant pathogenic mutation, yet only a fraction of carriers develop disease (incomplete penetrance), and phenotypes from mutations in the same gene range from mild to severe (variable expressivity). Here, we investigate underlying mechanisms for this heterogeneity: variable variant effect sizes, carrier polygenic backgrounds, and modulation of carrier effect by genetic background (epistasis). We leveraged exomes and clinical phenotypes from the UK Biobank and the Mt. Sinai Bio  Biobank to identify carriers of pathogenic variants affecting cardiometabolic traits. We employed recently developed methods to study these cohorts, observing strong statistical support and clinical translational potential for all three mechanisms of variable penetrance and expressivity. For example, scores from our recent model of variant pathogenicity were tightly correlated with phenotype amongst clinical variant carriers, they predicted effects of variants of unknown significance, and they distinguished gain- from loss-of-function variants. We also found that polygenic scores predicted phenotypes amongst pathogenic carriers and that epistatic effects can exceed main carrier effects by an order of magnitude.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37537905,
title = {Genetic counseling in diabetes mellitus: A practice resource of the National Society of Genetic Counselors},
author = {Kristin A Maloney and Elizabeth Mizerik and Robin H King and Erin M McGinnis and Susan Perkowitz and Callie J Diamonstein and Andrew A Schmanski and Sheila Saliganan and Andrea G Shipper and Miriam S Udler and Yue Guan and Toni I Pollin},
doi = {10.1002/jgc4.1744},
issn = {1573-3599},
year  = {2023},
date = {2023-08-01},
journal = {J Genet Couns},
abstract = {Diabetes mellitus is a group of diseases characterized by hyperglycemia and its consequences, affecting over 34 million individuals in the United States and 422 million worldwide. While most diabetes is polygenic and is classified as type 1 (T1D), type 2 (T2D), or gestational diabetes (GDM), at least 0.4% of all diabetes is monogenic in nature. Correct diagnosis of monogenic diabetes has important implications for glycemic management and genetic counseling. We provide this Practice Resource to familiarize the genetic counseling community with (1) the existence of monogenic diabetes, (2) how it differs from more common polygenic/complex diabetes types, (3) the advantage of a correct diagnosis, and (4) guidance for identifying, counseling, and testing patients and families with suspected monogenic diabetes. This document is intended for genetic counselors and other healthcare professionals providing clinical services in any setting, with the goal of maximizing the likelihood of a correct diagnosis of monogenic diabetes and access to related care.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37548801,
title = {A Potential Source of Bias in Group-Level EEG Microstate Analysis},
author = {Michael Murphy and Jun Wang and Chenguang Jiang and Lei A Wang and Nataliia Kozhemiako and Yining Wang and  and Jen Q Pan and Shaun M Purcell},
doi = {10.1007/s10548-023-00992-7},
issn = {1573-6792},
year  = {2023},
date = {2023-08-01},
journal = {Brain Topogr},
abstract = {Microstate analysis is a promising technique for analyzing high-density electroencephalographic data, but there are multiple questions about methodological best practices. Between and within individuals, microstates can differ both in terms of characteristic topographies and temporal dynamics, which leads to analytic challenges as the measurement of microstate dynamics is dependent on assumptions about their topographies. Here we focus on the analysis of group differences, using simulations seeded on real data from healthy control subjects to compare approaches that derive separate sets of maps within subgroups versus a single set of maps applied uniformly to the entire dataset. In the absence of true group differences in either microstate maps or temporal metrics, we found that using separate subgroup maps resulted in substantially inflated type I error rates. On the other hand, when groups truly differed in their microstate maps, analyses based on a single set of maps confounded topographic effects with differences in other derived metrics. We propose an approach to alleviate both classes of bias, based on a paired analysis of all subgroup maps. We illustrate the qualitative and quantitative impact of these issues in real data by comparing waking versus non-rapid eye movement sleep microstates. Overall, our results suggest that even subtle chance differences in microstate topography can have profound effects on derived microstate metrics and that future studies using microstate analysis should take steps to mitigate this large source of error.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37526719,
title = {Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry},
author = {Elizabeth Jordan and Daniel D Kinnamon and Garrie J Haas and Mark Hofmeyer and Evan Kransdorf and Gregory A Ewald and Alanna A Morris and Anjali Owens and Brian Lowes and Douglas Stoller and W H Wilson Tang and Sonia Garg and Barry H Trachtenberg and Palak Shah and Salpy V Pamboukian and Nancy K Sweitzer and Matthew T Wheeler and Jane E Wilcox and Stuart Katz and Stephen Pan and Javier Jimenez and Daniel P Fishbein and Frank Smart and Jessica Wang and Stephen S Gottlieb and Daniel P Judge and Charles K Moore and Jonathan O Mead and Natalie Hurst and Jinwen Cao and Gordon S Huggins and Jason Cowan and Hanyu Ni and Heidi L Rehm and Gail P Jarvik and Matteo Vatta and Wylie Burke and Ray E Hershberger and },
doi = {10.1001/jama.2023.11970},
issn = {1538-3598},
year  = {2023},
date = {2023-08-01},
journal = {JAMA},
volume = {330},
number = {5},
pages = {432--441},
abstract = {IMPORTANCE: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients.nnOBJECTIVE: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM.nnDESIGN: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance.nnEXPOSURE: Presence of DCM.nnMAIN OUTCOMES AND MEASURES: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic).nnRESULTS: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001).nnCONCLUSION AND RELEVANCE: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37485871,
title = {Usability and feasibility of PreventS-MD web app for stroke prevention},
author = {Valery L Feigin and Rita Krishnamurthi and Oleg Medvedev and Alexander Merkin and Balakrishnan Nair and Michael Kravchenko and Shabnam Jalili-Moghaddam and Suzanne Barker-Collo and Yogini Ratnasabapathy and Luke Skinner and Mayowa Owolabi and Bo Norrving and Perminder S Sachdev and Bruce Arroll and Michael Brainin and Amanda Thrift and Graeme J Hankey and },
doi = {10.1177/17474930231190745},
issn = {1747-4949},
year  = {2023},
date = {2023-08-01},
journal = {Int J Stroke},
pages = {17474930231190745},
abstract = {BACKGROUND: Most strokes and cardiovascular diseases (CVDs) are potentially preventable if their risk factors are identified and well controlled. Digital platforms, such as the PreventS-MD web app (PreventS-MD) may aid health care professionals (HCPs) in assessing and managing risk factors and promoting lifestyle changes for their patients.nnMETHODS: This is a mixed-methods cross-sectional two-phase survey using a largely positivist (quantitative and qualitative) framework. During Phase 1, a prototype of PreventS-MD was tested internationally by 59 of 69 consenting HCPs of different backgrounds, age, sex, working experience, and specialties using hypothetical data. Collected comments/suggestions from the study HCPs in Phase 1 were reviewed and implemented. In Phase 2, a near-final version of PreventS-MD was developed and tested by 58 of 72 consenting HCPs using both hypothetical and real patient (n = 10) data. Qualitative semi-structured interviews with real patients (n = 10) were conducted, and 1 month adherence to the preventive recommendations was assessed by self-reporting. The four System Usability Scale (SUS) groups of scores (0-50 unacceptable; 51-68 poor; 68-80.3 good; >80.3 excellent) were used to determine usability of PreventS-MD.nnFINDINGS: Ninety-nine HCPs from 27 countries (45% from low- to middle-income countries) participated in the study, and out of them, 10 HCPs were involved in the development of PreventS before the study, and therefore were not involved in the survey. Of the remaining 89 HCPs, 69 consented to the first phase of the survey, and 59 of them completed the first phase of the survey (response rate 86%), and 58 completed the second phase of the survey (response rate 84%). The SUS scores supported good usability of the prototype (mean score = 80.2; 95% CI [77.0-84.0]) and excellent usability of the final version of PreventS-MD (mean score = 81.7; 95% CI [79.1-84.3]) in the field. Scores were not affected by the age, sex, working experience, or specialty of the HCPs. One-month follow-up of the patients confirmed the high level of satisfaction/acceptability of PreventS-MD and (100%) adherence to the recommendations.nnINTERPRETATION: The PreventS-MD web app has a high level of usability, feasibility, and satisfaction by HCPs and individuals at risk of stroke/CVD. Individuals at risk of stroke/CVD demonstrated a high level of confidence and motivation in following and adhering to preventive recommendations generated by PreventS-MD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37306871,
title = {Migraine, chronic kidney disease and kidney function: observational and genetic analyses},
author = {Wenqiang Zhang and Li Zhang and Luo Yang and Chenghan Xiao and Xueyao Wu and Peijing Yan and Huijie Cui and Chao Yang and Jingwei Zhu and Xuan Wu and Mingshuang Tang and Yutong Wang and Lin Chen and Yunjie Liu and Yanqiu Zou and Ling Zhang and Chunxia Yang and Yuqin Yao and Jiayuan Li and Zhenmi Liu and Ben Zhang and Xia Jiang and },
doi = {10.1007/s00439-023-02575-9},
issn = {1432-1203},
year  = {2023},
date = {2023-08-01},
journal = {Hum Genet},
volume = {142},
number = {8},
pages = {1185--1200},
abstract = {Epidemiological studies demonstrate an association between migraine and chronic kidney disease (CKD), while the genetic basis underlying the phenotypic association has not been investigated. We aimed to help avoid unnecessary interventions in individuals with migraine through the investigation of phenotypic and genetic relationships underlying migraine, CKD, and kidney function. We first evaluated phenotypic associations using observational data from UK Biobank (N = 255,896). We then investigated genetic relationships leveraging genomic data in European ancestry for migraine (N/N = 48,975/540,381), CKD (N/N = 41,395/439,303), and two traits of kidney function (estimated glomerular filtration rate [eGFR, N = 567,460] and urinary albumin-to-creatinine ratio [UACR, N = 547,361]). Observational analyses suggested no significant association of migraine with the risk of CKD (HR = 1.13, 95% CI = 0.85-1.50). While we did not find any global genetic correlation in general, we identified four specific genomic regions showing significant for migraine with eGFR. Cross-trait meta-analysis identified one candidate causal variant (rs1047891) underlying migraine, CKD, and kidney function. Transcriptome-wide association study detected 28 shared expression-trait associations between migraine and kidney function. Mendelian randomization analysis suggested no causal effect of migraine on CKD (OR = 1.03, 95% CI = 0.98-1.09; P = 0.28). Despite a putative causal effect of migraine on an increased level of UACR (log-scale-beta = 0.02, 95% CI = 0.01-0.04; P = 1.92 × 10), it attenuated to null when accounting for both correlated and uncorrelated pleiotropy. Our work does not find evidence supporting a causal association between migraine and CKD. However, our study highlights significant biological pleiotropy between migraine and kidney function. The value of a migraine prophylactic treatment for reducing future CKD in people with migraine is likely limited.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37500730,
title = {Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders},
author = {Alfredo M Valencia and Akshay Sankar and Pleuntje J van der Sluijs and F Kyle Satterstrom and Jack Fu and Michael E Talkowski and Samantha A Schrier Vergano and Gijs W E Santen and Cigall Kadoch},
doi = {10.1038/s41588-023-01451-6},
issn = {1546-1718},
year  = {2023},
date = {2023-08-01},
journal = {Nat Genet},
volume = {55},
number = {8},
pages = {1400--1412},
abstract = {DNA sequencing-based studies of neurodevelopmental disorders (NDDs) have identified a wide range of genetic determinants. However, a comprehensive analysis of these data, in aggregate, has not to date been performed. Here, we find that genes encoding the mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling protein complexes harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes. Non-truncating NDD-associated protein variants predominantly disrupt the cBAF subcomplex and cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp module and DNA-binding domains. Although over 70% of the residues perturbed in NDDs overlap with those mutated in cancer, ~60% of amino acid changes are NDD-specific. These findings provide a foundation to functionally group variants and link complex aberrancies to phenotypic severity, serving as a resource for the chromatin, clinical genetics and neurodevelopment communities.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37693435,
title = {Comorbidity Profiles of Posttraumatic Stress Disorder Across the Medical Phenome},
author = {Emily M Hicks and Maria Niarchou and Slavina Goleva and Dia Kabir and Julia Ciarcia and  and Jordan W Smoller and Lea K Davis and Caroline M Nievergelt and Karestan C Koenen and Laura M Huckins and Karmel W Choi},
doi = {10.1101/2023.08.25.23294572},
year  = {2023},
date = {2023-08-01},
journal = {medRxiv},
abstract = {BACKGROUND: Prior epidemiological research has linked PTSD with specific physical health problems, but the comprehensive landscape of medical conditions associated with PTSD remains uncharacterized. Electronic health records (EHR) provide an opportunity to overcome prior clinical knowledge gaps and uncover associations with biological relevance that potentially vary by sex.nnMETHODS: PTSD was defined among biobank participants (total N=123,365) in a major healthcare system using two ICD code-based definitions: broad (1+ PTSD or acute stress codes versus 0; N  =14,899) and narrow (2+ PTSD codes versus 0; N  =3,026). Using a phenome-wide association (PheWAS) design, we tested associations between each PTSD definition and all prevalent disease umbrella categories, i.e., phecodes. We also conducted sex-stratified PheWAS analyses including a sex-by-diagnosis interaction term in each logistic regression.nnRESULTS: A substantial number of phecodes were significantly associated with PTSD  (61%) and PTSD  (83%). While top associations were shared between the two definitions, PTSD  captured 334 additional phecodes not significantly associated with PTSD  and exhibited a wider range of significantly associated phecodes across various categories, including respiratory, genitourinary, and circulatory conditions. Sex differences were observed, in that PTSD  was more strongly associated with osteoporosis, respiratory failure, hemorrhage, and pulmonary heart disease among male patients, and with urinary tract infection, acute pharyngitis, respiratory infections, and overweight among female patients.nnCONCLUSIONS: This study provides valuable insights into a diverse range of comorbidities associated with PTSD, including both known and novel associations, while highlighting the influence of sex differences and the impact of defining PTSD using EHR.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36705426,
title = {Pleiotropy analysis between lobar intracerebral hemorrhage and CSF β-amyloid highlights new and established associations},
author = {Sandro Marini and Jaeyoon Chung and Xudong Han and Xinyu Sun and Livia Parodi and Lindsay A Farrer and Jonathan Rosand and Jose Rafael Romero and Christopher D Anderson},
doi = {10.1177/17474930231155816},
issn = {1747-4949},
year  = {2023},
date = {2023-08-01},
journal = {Int J Stroke},
volume = {18},
number = {7},
pages = {804--811},
abstract = {BACKGROUND AND AIMS: Combining biologically related traits in genome-wide association studies (GWAS) increases the power for genetic discovery. Given the established relationship between lobar intracerebral hemorrhage (ICH) and cerebral amyloid angiopathy (CAA), and between the latter and levels of cerebrospinal fluid amyloid-β 42 (CSF-Aβ42), we leveraged genetic predisposition for lower CSF-Aβ42 levels as a proxy phenotype for CAA to identify new genes associated with lobar ICH.nnMETHODS: We used publicly available GWAS data for CSF-Aβ42 levels (n = 3146) and for lobar ICH (n = 2094). First, we evaluated the association between lobar ICH risk and CSF-Aβ42 in lobar ICH patients using a polygenic risk score (PRS) for CSF-Aβ42. Next, we conducted multi-trait analysis of GWAS (MTAG) for pleiotropy analysis of lobar ICH and CSF-Aβ42. MTAG results were further tested using Expression Quantitative Trait Locus and Differential Gene Expression Analyses.nnRESULTS: CSF-Aβ42 PRS was associated with lobar ICH risk (p = 0.04). MTAG analysis identified a novel association within  (rs1007589; minor allele frequency = 0.09; MTAG p = 5.4 × 10; lobar ICH odds ratio = 1.4 and p = 2.4 × 10; CSF-Aβ42 β = -0.03 and p = 4.5 × 10). rs1007589 was significantly associated with the expression levels of  in temporal and occipital cortices, regions known to preferentially accumulate microhemorrhages in CAA.nnCONCLUSION: Our pleiotropy analysis suggested a variant possibly implicated with lobar ICH driven by amyloid-related mechanisms in  and associated with differential expression in brain regions characteristically affected by CAA. CDH9 is one subtype of the cadherin superfamily, which regulates intercellular adhesion, is involved in blood-brain barrier integrity, and is elevated in Alzheimer's disease patients. Further analyses are warranted to understand the effects of the variant on the pathogenesis of ICH and its clinical significance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37604661,
title = {Association Between Hematoma Expansion Severity and Outcome and Its Interaction With Baseline Intracerebral Hemorrhage Volume},
author = {Andrea Morotti and Gregoire Boulouis and Jawed Nawabi and Qi Li and Andreas Charidimou and Marco Pasi and Frieder Schlunk and Ashkan Shoamanesh and Aristeidis H Katsanos and Federico Mazzacane and Giorgio Busto and Francesco Arba and Laura Brancaleoni and Sebastiano Giacomozzi and Luigi Simonetti and Andrew D Warren and Michele Laudisi and Anna Cavallini and Edip Gurol and Anand Viswanathan and Andrea Zini and Ilaria Casetta and Enrico Fainardi and Steven M Greenberg and Alessandro Padovani and Jonathan Rosand and Joshua Goldstein},
doi = {10.1212/WNL.0000000000207728},
issn = {1526-632X},
year  = {2023},
date = {2023-08-01},
journal = {Neurology},
abstract = {BACKGROUND AND OBJECTIVE: Hematoma expansion (HE) is a major determinant of neurological deterioration and poor outcome in intracerebral hemorrhage (ICH) and represents an appealing therapeutic target. We analyzed the prognostic effect of different degrees of HE.nnMETHODS: retrospective analysis of ICH patients admitted at eight academic institutions in Italy, Germany, Canada, China and United States. All patients underwent baseline and follow-up imaging for HE assessment. Relative HE (rHE) was classified as follows: (none < 0%), mild (0-33%), moderate (33.1-66%) and severe (> 66%). Absolute HE (aHE) was classified as none (< 0 mL), mild (0-6.0 mL), moderate (6.1-12.5 mL) and severe (> 12.5 mL). Predictors of poor functional outcome (90 days modified Rankin Scale 4-6) were explored with logistic regression.nnRESULTS: We included 2163 subjects, of whom 1211 (56.7%) had poor outcome. The occurrence of severe aHE or rHE was more common in patients with unfavorable outcome (13.9% vs 6.5%, p<0.001 and 18.3% vs 7.2 %, p<0.001 respectively). This association was confirmed in logistic regression (rHE OR 1.98, 95% CI 1.38-2.82, p<0.001; aHE odds ratio (OR)1.73,95% confidence interval (CI) 1.23-2.45, p=0.002) while there was no association between mild or moderate HE and poor outcome. The association between severe HE and poor outcome was significant only in patients with baseline ICH volume below 30 mL.nnDISCUSSION: The strongest association between HE and outcome was observed in patients with smaller initial volume experiencing severe HE. These findings may inform clinical trial design and guide clinicians in selecting patients for anti-expansion therapies.==========.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37601975,
title = {Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent  and  disruptions},
author = {Eduardo A Maury and Maxwell A Sherman and Giulio Genovese and Thomas G Gilgenast and Tushar Kamath and S J Burris and Prashanth Rajarajan and Erin Flaherty and Schahram Akbarian and Andrew Chess and Steven A McCarroll and Po-Ru Loh and Jennifer E Phillips-Cremins and Kristen J Brennand and Evan Z Macosko and James T R Walters and Michael O'Donovan and Patrick Sullivan and  and  and Jonathan Sebat and Eunjung A Lee and Christopher A Walsh},
doi = {10.1016/j.xgen.2023.100356},
issn = {2666-979X},
year  = {2023},
date = {2023-08-01},
journal = {Cell Genom},
volume = {3},
number = {8},
pages = {100356},
abstract = {While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)-present in some but not all cells-remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e-4), with recurrent somatic deletions of exons 1-5 of the  gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding -regulatory elements upon 5' deletions in . We also observed recurrent intragenic deletions of , encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that  is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37312453,
title = {Rescue of hearing by adenine base editing in a humanized mouse model of Usher syndrome type 1F},
author = {Cole W Peters and Killian S Hanlon and Maryna V Ivanchenko and Eric Zinn and Elizabeth F Linarte and Yaqiao Li and Jonathan M Levy and David R Liu and Benjamin P Kleinstiver and Artur A Indzhykulian and David P Corey},
doi = {10.1016/j.ymthe.2023.06.007},
issn = {1525-0024},
year  = {2023},
date = {2023-08-01},
journal = {Mol Ther},
volume = {31},
number = {8},
pages = {2439--2453},
abstract = {Usher syndrome type 1F (USH1F), characterized by congenital lack of hearing and balance and progressive loss of vision, is caused by mutations in the PCDH15 gene. In the Ashkenazi population, a recessive truncation mutation accounts for a large proportion of USH1F cases. The truncation is caused by a single C→T mutation, which converts an arginine codon to a stop (R245X). To test the potential for base editors to revert this mutation, we developed a humanized Pcdh15 mouse model for USH1F. Mice homozygous for the R245X mutation were deaf and exhibited profound balance deficits, while heterozygous mice were unaffected. Here we show that an adenine base editor (ABE) is capable of reversing the R245X mutation to restore the PCDH15 sequence and function. We packaged a split-intein ABE into dual adeno-associated virus (AAV) vectors and delivered them into cochleas of neonatal USH1F mice. Hearing was not restored in a Pcdh15 constitutive null mouse despite base editing, perhaps because of early disorganization of cochlear hair cells. However, injection of vectors encoding the split ABE into a late-deletion conditional Pcdh15 knockout rescued hearing. This study demonstrates the ability of an ABE to correct the PCDH15 R245X mutation in the cochlea and restore hearing.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37531033,
title = {Acetylglutamine Differentially Associated with First-Time Versus Recurrent Stroke},
author = {Naruchorn Kijpaisalratana and Zsuzsanna Ament and Amit Patki and Varun M Bhave and Alana C Jones and Ana-Lucia Garcia Guarniz and Catharine A Couch and Mary Cushman and D Leann Long and M Ryan Irvin and W Taylor Kimberly},
doi = {10.1007/s12975-023-01181-1},
issn = {1868-601X},
year  = {2023},
date = {2023-08-01},
journal = {Transl Stroke Res},
abstract = {Approximately one-quarter of strokes occur in individuals with prior stroke. Despite the advancement in secondary stroke prevention, the long-term risk of recurrent stroke has remained unchanged. The objective of this study was to identify metabolite risk markers that are associated with recurrent stroke. We performed targeted metabolomic profiling of 162 metabolites by liquid chromatography-tandem mass spectrometry in baseline plasma in a stroke case-cohort study nested within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, an observational cohort study of 30,239 individuals aged 45 and older enrolled in 2003-2007. Weighted Cox proportional hazard models were used to identify metabolites that had a differential effect on first-time versus recurrent stroke using an interaction term between metabolite and prior stroke at baseline (yes or no). The study included 1391 incident stroke cases identified during 7.1 ± 4.5 years of follow-up and 1050 participants in the random cohort sample. Among 162 metabolites, 13 candidates had a metabolite-by-prior stroke interaction at a p-value <0.05, with one metabolite, acetylglutamine, surpassing the Bonferroni adjusted p-value threshold (p for interaction = 5.78 × 10). In an adjusted model that included traditional stroke risk factors, acetylglutamine was associated with recurrent stroke (HR = 2.27 per SD increment, 95% CI = 1.60-3.20, p = 3.52 × 10) but not with first-time stroke (HR = 0.96 per SD increment, 95% CI = 0.87-1.06, p = 0.44). Acetylglutamine was associated with recurrent stroke but not first-time stroke, independent of traditional stroke risk factors. Future studies are warranted to elucidate the pathogenesis of acetylglutamine and recurrent stroke risk.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36869767,
title = {Haplotype-specific MAPK3 expression in 16p11.2 deletion contributes to variable neurodevelopment},
author = {Fang Liu and Chen Liang and Zhengchang Li and Sen Zhao and Haiming Yuan and Ruen Yao and Zailong Qin and Shaofang Shangguan and Shujie Zhang and Li-Ping Zou and Qian Chen and Zhijie Gao and Suiwen Wen and Jing Peng and Fei Yin and Fei Chen and Xiaoxia Qiu and Jingsi Luo and Yingjun Xie and Dian Lu and Yu Zhang and Hua Xie and Guozhuang Li and Terry Jianguo Zhang and Pengfei Luan and Hongying Wang and Xiaodai Cui and Hailiang Huang and Ruize Liu and Xiaofang Sun and Chao Chen and Nan Wu and Jian Wang and Chunyu Liu and Yiping Shen and James F Gusella and Xiaoli Chen},
doi = {10.1093/brain/awad071},
issn = {1460-2156},
year  = {2023},
date = {2023-08-01},
journal = {Brain},
volume = {146},
number = {8},
pages = {3347--3363},
abstract = {Recurrent proximal 16p11.2 deletion (16p11.2del) is a risk factor for diverse neurodevelopmental disorders with incomplete penetrance and variable expressivity. Although investigation with human induced pluripotent stem cell models has confirmed disruption of neuronal development in 16p11.2del neuronal cells, which genes are responsible for abnormal cellular phenotypes and what determines the penetrance of neurodevelopmental abnormalities are unknown. We performed haplotype phasing of the 16p11.2 region in a 16p11.2del neurodevelopmental disorders cohort and generated human induced pluripotent stem cells for two 16p11.2del families with distinct residual haplotypes and variable neurodevelopmental disorder phenotypes. Using transcriptomic profiles and cellular phenotypes of the human induced pluripotent stem cell-differentiated cortex neuronal cells, we revealed MAPK3 to be a contributor to dysfunction in multiple pathways related to early neuronal development, with altered soma and electrophysiological properties in mature neuronal cells. Notably, MAPK3 expression in 16p11.2del neuronal cells varied on the basis of a 132 kb 58 single nucleotide polymorphism (SNP) residual haplotype, with the version composed entirely of minor alleles associated with reduced MAPK3 expression. Ten SNPs on the residual haplotype were mapped to enhancers of MAPK3. We functionally validated six of these SNPs by luciferase assay, implicating them in the residual haplotype-specific differences in MAPK3 expression via cis-regulation. Finally, the analysis of three different cohorts of 16p11.2del subjects showed that this minor residual haplotype is associated with neurodevelopmental disorder phenotypes in 16p11.2del carriers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37605270,
title = {An atlas of associations between 14 micronutrients and 22 cancer outcomes: Mendelian randomization analyses},
author = {Jong Yeob Kim and Minku Song and Min Seo Kim and Pradeep Natarajan and Ron Do and Woojae Myung and Hong-Hee Won},
doi = {10.1186/s12916-023-03018-y},
issn = {1741-7015},
year  = {2023},
date = {2023-08-01},
journal = {BMC Med},
volume = {21},
number = {1},
pages = {316},
abstract = {BACKGROUND: Micronutrients, namely vitamins and minerals, are associated with cancer outcomes; however, their reported effects have been inconsistent across studies. We aimed to identify the causally estimated effects of micronutrients on cancer by applying the Mendelian randomization (MR) method, using single-nucleotide polymorphisms associated with micronutrient levels as instrumental variables.nnMETHODS: We obtained instrumental variables of 14 genetically predicted micronutrient levels and applied two-sample MR to estimate their causal effects on 22 cancer outcomes from a meta-analysis of the UK Biobank (UKB) and FinnGen cohorts (overall cancer and 21 site-specific cancers, including breast, colorectal, lung, and prostate cancer), in addition to six major cancer outcomes and 20 cancer subset outcomes from cancer consortia. We used sensitivity MR methods, including weighted median, MR-Egger, and MR-PRESSO, to assess potential horizontal pleiotropy or heterogeneity. Genome-wide association summary statistical data of European descent were used for both exposure and outcome data, including up to 940,633 participants of European descent with 133,384 cancer cases.nnRESULTS: In total, 672 MR tests (14 micronutrients × 48 cancer outcomes) were performed. The following two associations met Bonferroni significance by the number of associations (P < 0.00016) in the UKB plus FinnGen cohorts: increased risk of breast cancer with magnesium levels (odds ratio [OR] = 1.281 per 1 standard deviation [SD] higher magnesium level, 95% confidence interval [CI] = 1.151 to 1.426, P < 0.0001) and increased risk of colorectal cancer with vitamin B12 level (OR = 1.22 per 1 SD higher vitamin B12 level, 95% CI = 1.107 to 1.345, P < 0.0001). These two associations remained significant in the analysis of the cancer consortia. No significant heterogeneity or horizontal pleiotropy was observed. Micronutrient levels were not associated with overall cancer risk.nnCONCLUSIONS: Our results may aid clinicians in deciding whether to regulate the intake of certain micronutrients, particularly in high-risk groups without nutritional deficiencies, and may help in the design of future clinical trials.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37086804,
title = {A 50-state survey study of thoughts of suicide and social isolation among older adults in the United States},
author = {Nili Solomonov and Jon Green and Alexi Quintana and Jennifer Lin and Katherine Ognyanova and Mauricio Santillana and James N Druckman and Matthew A Baum and David Lazer and Faith M Gunning and Roy H Perlis},
doi = {10.1016/j.jad.2023.04.038},
issn = {1573-2517},
year  = {2023},
date = {2023-08-01},
journal = {J Affect Disord},
volume = {334},
pages = {43--49},
abstract = {BACKGROUND: We aimed to characterize the prevalence of social disconnection and thoughts of suicide among older adults in the United States, and examine the association between them in a large naturalistic study.nnMETHODS: We analyzed data from 6 waves of a fifty-state non-probability survey among US adults conducted between February and December 2021. The internet-based survey collected the PHQ-9, as well as multiple measures of social connectedness. We applied multiple logistic regression to analyze the association between presence of thoughts of suicide and social disconnection. Exploratory analysis, using generalized random forests, examined heterogeneity of effects across sociodemographic groups.nnRESULTS: Of 16,164 survey respondents age 65 and older, mean age was 70.9 (SD 5.0); the cohort was 61.4 % female and 29.6 % male; 2.0 % Asian, 6.7 % Black, 2.2 % Hispanic, and 86.8 % White. A total of 1144 (7.1 %) reported thoughts of suicide at least several days in the prior 2 week period. In models adjusted for sociodemographic features, households with 3 or more additional members (adjusted OR 1.73, 95 % CI 1.28-2.33) and lack of social supports, particularly emotional supports (adjusted OR 2.60, 95 % CI 2.09-3.23), were independently associated with greater likelihood of reporting such thoughts, as was greater reported loneliness (adjusted OR 1.75, 95 % CI 1.64-1.87). The effects of emotional support varied significantly across sociodemographic groups.nnCONCLUSIONS: Thoughts of suicide are common among older adults in the US, and associated with lack of social support, but not with living alone.nnTRIAL REGISTRATION: NA.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37338115,
title = {Healthcare experiences of patients with Down syndrome from primarily Spanish-speaking households},
author = {Jeanhee Chung and Kavita Krell and Albert Pless and Carie Michael and Amy Torres and Sandra Baker and Jasmine M Blake and Kelli Caughman and Sarah Cullen and Maureen Gallagher and Roxanne Hoke-Chandler and Julius Maina and Diana McLuckie and Kate O'Neill and Angeles Peña and Dina Royal and Michelle Slape and Noemi Alice Spinazzi and Carlos G Torres and Brian G Skotko},
doi = {10.1002/ajmg.a.63250},
issn = {1552-4833},
year  = {2023},
date = {2023-08-01},
journal = {Am J Med Genet A},
volume = {191},
number = {8},
pages = {2132--2141},
abstract = {We report on the health care experiences of individuals with Down syndrome (DS) from families who are primarily Spanish-speaking. Data were collected through three methods: (1) a nationally distributed, 20-item survey, (2) two focus groups with seven family caregivers of individuals with DS who self-identified as living in primarily Spanish speaking households, and (3) 20 interviews with primary care providers (PCPs) who care for patients who are underrepresented minorities. Standard summary statistics were used to analyze the quantitative survey results. Focus group and interview transcripts, as well as an open-ended response question in the survey, were analyzed using qualitative coding methods to identify key themes. Both caregivers and PCPs described how language barriers make giving and receiving quality care difficult. Caregivers additionally described condescending, discriminatory treatment within the medical system and shared feelings of caregiver stress and social isolation. Challenges to care experienced by families of individuals with DS are compounded for Spanish-speaking families, where the ability to build trust with providers and in the health care system may be compromised by cultural and language differences, systemic issues (lack of time or inability to craft more nuanced schedules so that patients with higher needs are offered more time), mistrust, and sometimes, overt racism. Building this trust is critical to improve access to information, care options, and research opportunities, especially for this community that depends on their clinicians and nonprofit groups as trusted messengers. More study is needed to understand how to better reach out to these communities through primary care clinician networks and nonprofit organizations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37386106,
title = {Patterns of item nonresponse behaviour to survey questionnaires are systematic and associated with genetic loci},
author = {Gianmarco Mignogna and Caitlin E Carey and Robbee Wedow and Nikolas Baya and Mattia Cordioli and Nicola Pirastu and Rino Bellocco and Kathryn Fiuza Malerbi and Michel G Nivard and Benjamin M Neale and Raymond K Walters and Andrea Ganna},
doi = {10.1038/s41562-023-01632-7},
issn = {2397-3374},
year  = {2023},
date = {2023-08-01},
journal = {Nat Hum Behav},
volume = {7},
number = {8},
pages = {1371--1387},
abstract = {Response to survey questionnaires is vital for social and behavioural research, and most analyses assume full and accurate response by participants. However, nonresponse is common and impedes proper interpretation and generalizability of results. We examined item nonresponse behaviour across 109 questionnaire items in the UK Biobank (N = 360,628). Phenotypic factor scores for two participant-selected nonresponse answers, 'Prefer not to answer' (PNA) and 'I don't know' (IDK), each predicted participant nonresponse in follow-up surveys (incremental pseudo-R = 0.056), even when controlling for education and self-reported health (incremental pseudo-R = 0.046). After performing genome-wide association studies of our factors, PNA and IDK were highly genetically correlated with one another (r = 0.73 (s.e. = 0.03)) and with education (r = -0.51 (s.e. = 0.03); r = -0.38 (s.e. = 0.02)), health (r = 0.51 (s.e. = 0.03); r = 0.49 (s.e. = 0.02)) and income (r = -0.57 (s.e. = 0.04); r = -0.46 (s.e. = 0.02)), with additional unique genetic associations observed for both PNA and IDK (P < 5 × 10). We discuss how these associations may bias studies of traits correlated with item nonresponse and demonstrate how this bias may substantially affect genome-wide association studies. While the UK Biobank data are deidentified, we further protected participant privacy by avoiding exploring non-response behaviour to single questions, assuring that no information can be used to associate results with any particular respondents.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37620596,
title = {Principles and methods for transferring polygenic risk scores across global populations},
author = {Linda Kachuri and Nilanjan Chatterjee and Jibril Hirbo and Daniel J Schaid and Iman Martin and Iftikhar J Kullo and Eimear E Kenny and Bogdan Pasaniuc and  and John S Witte and Tian Ge},
doi = {10.1038/s41576-023-00637-2},
issn = {1471-0064},
year  = {2023},
date = {2023-08-01},
journal = {Nat Rev Genet},
abstract = {Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine. However, PRSs that are developed in populations of predominantly European genetic ancestries can increase health disparities due to poor predictive performance in individuals of diverse and complex genetic ancestries. We describe genetic and modifiable risk factors that limit the transferability of PRSs across populations and review the strengths and weaknesses of existing PRS construction methods for diverse ancestries. Developing PRSs that benefit global populations in research and clinical settings provides an opportunity for innovation and is essential for health equity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36747613,
title = {A harmonized public resource of deeply sequenced diverse human genomes},
author = {Zan Koenig and Mary T Yohannes and Lethukuthula L Nkambule and Julia K Goodrich and Heesu Ally Kim and Xuefang Zhao and Michael W Wilson and Grace Tiao and Stephanie P Hao and Nareh Sahakian and Katherine R Chao and  and Heidi L Rehm and Benjamin M Neale and Michael E Talkowski and Mark J Daly and Harrison Brand and Konrad J Karczewski and Elizabeth G Atkinson and Alicia R Martin},
doi = {10.1101/2023.01.23.525248},
year  = {2023},
date = {2023-08-01},
journal = {bioRxiv},
abstract = {Underrepresented populations are often excluded from genomic studies due in part to a lack of resources supporting their analyses. The 1000 Genomes Project (1kGP) and Human Genome Diversity Project (HGDP), which have recently been sequenced to high coverage, are valuable genomic resources because of the global diversity they capture and their open data sharing policies. Here, we harmonized a high quality set of 4,096 whole genomes from HGDP and 1kGP with data from gnomAD and identified over 159 million high-quality SNVs, indels, and SVs. We performed a detailed ancestry analysis of this cohort, characterizing population structure and patterns of admixture across populations, analyzing site frequency spectra, and measuring variant counts at global and subcontinental levels. We also demonstrate substantial added value from this dataset compared to the prior versions of the component resources, typically combined via liftover and variant intersection; for example, we catalog millions of new genetic variants, mostly rare, compared to previous releases. In addition to unrestricted individual-level public release, we provide detailed tutorials for conducting many of the most common quality control steps and analyses with these data in a scalable cloud-computing environment and publicly release this new phased joint callset for use as a haplotype resource in phasing and imputation pipelines. This jointly called reference panel will serve as a key resource to support research of diverse ancestry populations.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36993580,
title = {Inferring compound heterozygosity from large-scale exome sequencing data},
author = {Michael H Guo and Laurent C Francioli and Sarah L Stenton and Julia K Goodrich and Nicholas A Watts and Moriel Singer-Berk and Emily Groopman and Philip W Darnowsky and Matthew Solomonson and Samantha Baxter and  and Grace Tiao and Benjamin M Neale and Joel N Hirschhorn and Heidi L Rehm and Mark J Daly and Anne O'Donnell-Luria and Konrad J Karczewski and Daniel G MacArthur and Kaitlin E Samocha},
doi = {10.1101/2023.03.19.533370},
year  = {2023},
date = {2023-08-01},
journal = {bioRxiv},
abstract = {Recessive diseases arise when both the maternal and the paternal copies of a gene are impacted by a damaging genetic variant in the affected individual. When a patient carries two different potentially causal variants in a gene for a given disorder, accurate diagnosis requires determining that these two variants occur on different copies of the chromosome (i.e., are in  ) rather than on the same copy (i.e. in  ). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. We developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in exome sequencing data from the Genome Aggregation Database (gnomAD v2, n=125,748). When applied to trio data where phase can be determined by transmission, our approach estimates phase with 95.7% accuracy and remains accurate even for very rare variants (allele frequency < 1x10  ). We also correctly phase 95.9% of variant pairs in a set of 293 patients with Mendelian conditions carrying presumed causal compound heterozygous variants. We provide a public resource of phasing estimates from gnomAD, including phasing estimates for coding variants across the genome and counts per gene of rare variants in  , that can aid interpretation of rare co-occurring variants in the context of recessive disease.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37327798,
title = {Association between the timing of childhood adversity and epigenetic patterns across childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort},
author = {Alexandre A Lussier and Yiwen Zhu and Brooke J Smith and Janine Cerutti and Jonah Fisher and Phillip E Melton and Natasha M Wood and Sarah Cohen-Woods and Rae-Chi Huang and Colter Mitchell and Lisa Schneper and Daniel A Notterman and Andrew J Simpkin and Andrew D A C Smith and Matthew J Suderman and Esther Walton and Caroline L Relton and Kerry J Ressler and Erin C Dunn},
doi = {10.1016/S2352-4642(23)00127-X},
issn = {2352-4650},
year  = {2023},
date = {2023-08-01},
journal = {Lancet Child Adolesc Health},
volume = {7},
number = {8},
pages = {532--543},
abstract = {BACKGROUND: Childhood adversity is a potent determinant of health across development and is associated with altered DNA methylation signatures, which might be more common in children exposed during sensitive periods in development. However, it remains unclear whether adversity has persistent epigenetic associations across childhood and adolescence. We aimed to examine the relationship between time-varying adversity (defined through sensitive period, accumulation of risk, and recency life course hypotheses) and genome-wide DNA methylation, measured three times from birth to adolescence, using data from a prospective, longitudinal cohort study.nnMETHODS: We first investigated the relationship between the timing of exposure to childhood adversity between birth and 11 years and blood DNA methylation at age 15 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort study. Our analytic sample included ALSPAC participants with DNA methylation data and complete childhood adversity data between birth and 11 years. We analysed seven types of adversity (caregiver physical or emotional abuse, sexual or physical abuse [by anyone], maternal psychopathology, one-adult households, family instability, financial hardship, and neighbourhood disadvantage) reported by mothers five to eight times between birth and 11 years. We used the structured life course modelling approach (SLCMA) to identify time-varying associations between childhood adversity and adolescent DNA methylation. Top loci were identified using an R threshold of 0·035 (ie, ≥3·5% of DNA methylation variance explained by adversity). We attempted to replicate these associations using data from the Raine Study and Future of Families and Child Wellbeing Study (FFCWS). We also assessed the persistence of adversity-DNA methylation associations we previously identified from age 7 blood DNA methylation into adolescence and the influence of adversity on DNA methylation trajectories from ages 0-15 years.nnFINDINGS: Of 13 988 children in the ALSPAC cohort, 609-665 children (311-337 [50-51%] boys and 298-332 [49-50%] girls) had complete data available for at least one of the seven childhood adversities and DNA methylation at 15 years. Exposure to adversity was associated with differences in DNA methylation at 15 years for 41 loci (R ≥0·035). Sensitive periods were the most often selected life course hypothesis by the SLCMA. 20 (49%) of 41 loci were associated with adversities occurring between age 3 and 5 years. Exposure to one-adult households was associated with differences in DNA methylation at 20 [49%] of 41 loci, exposure to financial hardship was associated with changes at nine (22%) loci, and physical or sexual abuse was associated with changes at four (10%) loci. We replicated the direction of associations for 18 (90%) of 20 loci associated with exposure to one-adult household using adolescent blood DNA methylation from the Raine Study and 18 (64%) of 28 loci using saliva DNA methylation from the FFCWS. The directions of effects for 11 one-adult household loci were replicated in both cohorts. Differences in DNA methylation at 15 years were not present at 7 years and differences identified at 7 years were no longer apparent by 15 years. We also identified six distinct DNA methylation trajectories from these patterns of stability and persistence.nnINTERPRETATION: These findings highlight the time-varying effect of childhood adversity on DNA methylation profiles across development, which might link exposure to adversity to potential adverse health outcomes in children and adolescents. If replicated, these epigenetic signatures could ultimately serve as biological indicators or early warning signs of initiated disease processes, helping identify people at greater risk for the adverse health consequences of childhood adversity.nnFUNDING: Canadian Institutes of Health Research, Cohort and Longitudinal Studies Enhancement Resources, EU's Horizon 2020, US National Institute of Mental Health.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37541186,
title = {Beyond the exome: What's next in diagnostic testing for Mendelian conditions},
author = {Monica H Wojcik and Chloe M Reuter and Shruti Marwaha and Medhat Mahmoud and Michael H Duyzend and Hayk Barseghyan and Bo Yuan and Philip M Boone and Emily E Groopman and Emmanuèle C Délot and Deepti Jain and Alba Sanchis-Juan and  and Lea M Starita and Michael Talkowski and Stephen B Montgomery and Michael J Bamshad and Jessica X Chong and Matthew T Wheeler and Seth I Berger and Anne O'Donnell-Luria and Fritz J Sedlazeck and Danny E Miller},
doi = {10.1016/j.ajhg.2023.06.009},
issn = {1537-6605},
year  = {2023},
date = {2023-08-01},
journal = {Am J Hum Genet},
volume = {110},
number = {8},
pages = {1229--1248},
abstract = {Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37314226,
title = {A de novo missense variant in EZH1 associated with developmental delay exhibits functional deficits in Drosophila melanogaster},
author = {Sharayu V Jangam and Lauren C Briere and Kristy L Jay and Jonathan C Andrews and Melissa A Walker and Lance H Rodan and Frances A High and  and Shinya Yamamoto and David A Sweetser and Michael F Wangler},
doi = {10.1093/genetics/iyad110},
issn = {1943-2631},
year  = {2023},
date = {2023-08-01},
journal = {Genetics},
volume = {224},
number = {4},
abstract = {EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo missense variant in EZH1 through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and an analogous somatic or germline mutation in EZH2 has been reported in patients with B-cell lymphoma or Weaver syndrome, respectively. Human EZH1/2 are homologous to fly Enhancer of zeste (E(z)), an essential gene in Drosophila, and the affected residue (p.A678 in humans, p.A691 in flies) is conserved. To further study this variant, we obtained null alleles and generated transgenic flies expressing wildtype [E(z)WT] and the variant [E(z)A691G]. When expressed ubiquitously the variant rescues null-lethality similar to the wildtype. Overexpression of E(z)WT induces homeotic patterning defects but notably the E(z)A691G variant leads to dramatically stronger morphological phenotypes. We also note a dramatic loss of H3K27me2 and a corresponding increase in H3K27me3 in flies expressing E(z)A691G, suggesting this acts as a gain-of-function allele. In conclusion, here we present a novel EZH1 de novo variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in Drosophila.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37517917,
title = {Advancing Understanding of Inequities in Rare Disease Genomics},
author = {Jillian G Serrano and Melanie O'Leary and Grace E VanNoy and Brian E Mangilog and Ingrid A Holm and Yarden S Fraiman and Heidi L Rehm and Anne O'Donnell-Luria and Monica H Wojcik},
doi = {10.1016/j.clinthera.2023.06.010},
issn = {1879-114X},
year  = {2023},
date = {2023-08-01},
journal = {Clin Ther},
volume = {45},
number = {8},
pages = {745--753},
abstract = {PURPOSE: Advances in genomic research have facilitated rare disease diagnosis for thousands of individuals. Unfortunately, the benefits of advanced genetic diagnostic technology are not distributed equitably among the population, as has been seen in many other health care contexts. Quantifying and describing inequities in genetic diagnostic yield is inherently challenging due to barriers to both clinical and research genetic testing. We therefore present an implementation protocol developed to expand access to our rare disease genomic research study and to further understand existing inequities.nnMETHODS AND FINDINGS: The Rare Genomes Project (RGP) at the Broad Institute of MIT and Harvard offers research genome sequencing to individuals with rare disease who remain genetically undiagnosed through direct interaction with the individual or family. This presents an opportunity for diagnosis beyond the clinical context, thus eliminating many barriers to access. An initial goal of RGP was to equalize access to genomic sequencing by decoupling testing access from proximity to a major medical center and physician referral. However, study participants over the initial 3 years of this project were predominantly white and well resourced. To further understand and address the lack of diversity within RGP, we developed a novel protocol embedded within the larger RGP study, in an approach informed by an implementation science framework. The aims of this protocol were: (1) to diversify recruitment and enrollment within RGP; (2) understand the process and context of implementing genomic medicine for rare disease diagnosis; and (3) investigate the value of a diagnosis for underserved populations.nnIMPLICATIONS: Improved understanding of existing inequities and potential strategies to address them are needed to advance equity in rare disease genetic diagnosis and research. In addition to the moral imperative of equity in genomic medicine, this approach is critical in order to fully understand the genomic underpinnings of rare disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37495702,
title = {Author Correction: A single-cell atlas of human and mouse white adipose tissue},
author = {Margo P Emont and Christopher Jacobs and Adam L Essene and Deepti Pant and Danielle Tenen and Georgia Colleluori and Angelica Di Vincenzo and Anja M Jørgensen and Hesam Dashti and Adam Stefek and Elizabeth McGonagle and Sophie Strobel and Samantha Laber and Saaket Agrawal and Gregory P Westcott and Amrita Kar and Molly L Veregge and Anton Gulko and Harini Srinivasan and Zachary Kramer and Eleanna De Filippis and Erin Merkel and Jennifer Ducie and Christopher G Boyd and William Gourash and Anita Courcoulas and Samuel J Lin and Bernard T Lee and Donald Morris and Adam Tobias and Amit V Khera and Melina Claussnitzer and Tune H Pers and Antonio Giordano and Orr Ashenberg and Aviv Regev and Linus T Tsai and Evan D Rosen},
doi = {10.1038/s41586-023-06445-2},
issn = {1476-4687},
year  = {2023},
date = {2023-08-01},
journal = {Nature},
volume = {620},
number = {7973},
pages = {E14},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37260376,
title = {Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich's ataxia},
author = {Tslil Ast and Hong Wang and Eizo Marutani and Fumiaki Nagashima and Rajeev Malhotra and Fumito Ichinose and Vamsi K Mootha},
doi = {10.1093/hmg/ddad091},
issn = {1460-2083},
year  = {2023},
date = {2023-08-01},
journal = {Hum Mol Genet},
volume = {32},
number = {16},
pages = {2600--2610},
abstract = {Friedreich's ataxia (FA) is a devastating, multi-systemic neurodegenerative disease affecting thousands of people worldwide. We previously reported that oxygen is a key environmental variable that can modify FA pathogenesis. In particular, we showed that chronic, continuous normobaric hypoxia (11% FIO2) prevents ataxia and neurological disease in a murine model of FA, although it did not improve cardiovascular pathology or lifespan. Here, we report the pre-clinical evaluation of seven 'hypoxia-inspired' regimens in the shFxn mouse model of FA, with the long-term goal of designing a safe, practical and effective regimen for clinical translation. We report three chief results. First, a daily, intermittent hypoxia regimen (16 h 11% O2/8 h 21% O2) conferred no benefit and was in fact harmful, resulting in elevated cardiac stress and accelerated mortality. The detrimental effect of this regimen is likely owing to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as we could blunt this toxicity by pharmacologically inhibiting polycythemia. Second, we report that more mild regimens of chronic hypoxia (17% O2) confer a modest benefit by delaying the onset of ataxia. Third, excitingly, we show that initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36094018,
title = {Testing lifecourse theories characterising associations between maternal depression and offspring depression in emerging adulthood: the Avon Longitudinal Study of Parents and Children},
author = {Rebecca E Lacey and Dawid Gondek and Brooke J Smith and Andrew D A C Smith and Erin C Dunn and Amanda Sacker},
doi = {10.1111/jcpp.13699},
issn = {1469-7610},
year  = {2023},
date = {2023-08-01},
journal = {J Child Psychol Psychiatry},
volume = {64},
number = {8},
pages = {1149--1158},
abstract = {BACKGROUND: Maternal depression is a major determinant of offspring mental health. Yet, little is understood about how the duration and timing of maternal depression shapes youth risk for depressive symptoms, which if understood could inform when best to intervene. This study aimed to determine how the timing and duration of maternal depression was related to offspring depression in emerging adulthood, and if these associations varied by sex.nnMETHODS: We analysed data from the Avon Longitudinal Study of Parents and Children (a prenatal cohort in the Avon area of England, 1991-2003), n = 3,301. We applied the structured lifecourse modelling approach to maternal depression (assessed at 13 points from prenatal period to adolescence) and emerging adult depressive symptoms (age 21). Lifecourse models assessed were accumulation (sum of timepoints when maternal depression was reported), sensitive periods (each period assessed as one during which maternal depression has a stronger effect) and instability (frequent fluctuations in maternal depression).nnRESULTS: Female adolescents (n = 2,132) had higher SMFQ scores (mean = 6.15, SD = 5.90) than males (n = 1,169, mean = 4.87, SD = 4.82). Maternal depression was most common in the infancy period (21.2% males; 21.4% females). For males, accumulation was the most appropriate lifecourse model; for each additional period of maternal depression, depressive symptoms in emerging adulthood increased by 0.11 (95% CI: 0.07, 0.15, one-sided p value ≤ .001). For females, exposure to maternal depression was associated with increasing depressive symptoms in emerging adulthood, with the largest effect in mid-childhood (increase of 0.27 units, 95% CI 0.03-0.50, p = .015 for difference between mid-childhood and other time-periods) and a smaller, equal effect at all other time-periods (increase of 0.07 units per time-period, 95% CI: 0.03-0.12, p = .002).nnCONCLUSIONS: This study highlights the importance of ongoing maternal depression for the development of depression in offspring through to emerging adulthood. Because long-term exposure to maternal depression was particularly important, early interventions are warranted.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37537264,
title = {A FinnGen pilot clinical recall study for Alzheimer's disease},
author = {Valtteri Julkunen and Claudia Schwarz and Juho Kalapudas and Merja Hallikainen and Aino-Kaisa Piironen and Arto Mannermaa and Hanna Kujala and Timo Laitinen and Veli-Matti Kosma and Teemu I Paajanen and Reetta Kälviäinen and Mikko Hiltunen and Sanna-Kaisa Herukka and Sari Kärkkäinen and Tarja Kokkola and Mia Urjansson and  and Markus Perola and Aarno Palotie and Eero Vuoksimaa and Heiko Runz},
doi = {10.1038/s41598-023-39835-7},
issn = {2045-2322},
year  = {2023},
date = {2023-08-01},
journal = {Sci Rep},
volume = {13},
number = {1},
pages = {12641},
abstract = {Successful development of novel therapies requires that clinical trials are conducted in patient cohorts with the highest benefit-to-risk ratio. Population-based biobanks with comprehensive health and genetic data from large numbers of individuals hold promise to facilitate identification of trial participants, particularly when interventions need to start while symptoms are still mild, such as for Alzheimer's disease (AD). This study describes a process for clinical recall studies from FinnGen. We demonstrate the feasibility to systematically ascertain customized clinical data from FinnGen participants with ICD10 diagnosis of AD or mild cognitive disorder (MCD) in a single-center cross-sectional study testing blood-based biomarkers and cognitive functioning in-person, computer-based and remote. As a result, 19% (27/140) of a pre-specified FinnGen subcohort were successfully recalled and completed the study. Hospital records largely validated registry entries. For 8/12 MCD patients, other reasons than AD were identified as underlying diagnosis. Cognitive measures correlated across platforms, with highest consistencies for dementia screening (r = 0.818) and semantic fluency (r = 0.764), respectively, for in-person versus telephone-administered tests. Glial fibrillary acidic protein (GFAP) (p < 0.002) and phosphorylated-tau 181 (pTau-181) (p < 0.020) most reliably differentiated AD from MCD participants. We conclude that informative, customized clinical recall studies from FinnGen are feasible.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37609315,
title = {The ABCD-GENE score influences vascular event rates in both users of clopidogrel and aspirin, as well as non-users of either drug in a population-based cohort study},
author = {Kaavya Narasimhalu and Ernst Mayerhofer and Livia Parodi and Marios K Georgakis and Deidre Anne De Silva and Jonathan Rosand and Christopher D Anderson},
doi = {10.1101/2023.08.06.23293732},
year  = {2023},
date = {2023-08-01},
journal = {medRxiv},
abstract = {BACKGROUND AND OBJECTIVES: Clopidogrel is an antiplatelet used in both primary and secondary prevention of cardiovascular diseases. It is a prodrug, requiring  for its metabolism to the active metabolite. The ABCD-GENE score, combining clinical attributes (age, body mass index, chronic kidney disease, diabetes mellitus), with genetic information (presence of 1 or 2 loss of function (LOF) alleles in the  gene) has been shown to identify patients with higher risk of recurrent cardiovascular events in high-risk populations undergoing percutaneous coronary intervention. We aimed to determine if the ABCD-GENE score or LOF alleles were associated with an increased risk of vascular events among clopidogrel users in a general population.nnMETHODS: We conducted a population based cohort study with UK Biobank's primary care prescription records to identify clopidogrel users. ABCD-GENE scores were calculated with closest available data from the first date of clopidogrel prescription. The number of LOF alleles present, and the clinical component ABCD, were separate exposures. The outcome of interest was a composite endpoint of vascular events comprised of myocardial infarction, ischemic stroke, and death due to either of these. We performed Cox proportional hazards models with clopidogrel as a time varying exposure to predict hazards of these outcomes. In order to determine the drug specificity of these exposures, the analyses were repeated in aspirin users, and in non-users of either aspirin or clopidogrel.nnRESULTS: Among 11,248 clopidogrel users, 3,365 (30%) developed a vascular event over a mean follow-up of 5.95±3.94 years. ABCD-GENE score ≥10 was associated with an increased risk of vascular events (HR 1.13, 95% CI 1.03-1.23). In aspirin users, and in non-users of either aspirin or clopidogrel, the ABCD-GENE score was also associated with increased risk of vascular events. In clopidogrel users, aspirin users, and non-users of either drug, the ABCD score was associated with increased risk of vascular events. The presence of two  LOF alleles was associated with an increased risk of vascular events in aspirin and non-users but not in clopidogrel users.nnDISCUSSION: In this population-based cohort study, the ABCD-GENE score was associated with an increased risk of vascular events in clopidogrel users, aspirin users, and in non-users of either drug. The clinical component, ABCD was also associated with an increased risk of vascular events in all three groups. This suggests that the ABCD-GENE score is not specific to clopidogrel users in identifying persons at high risk of vascular events in a general sample with low baseline  LOF allele frequency.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37609130,
title = {A genome-wide atlas of human cell morphology},
author = {Meraj Ramezani and Julia Bauman and Avtar Singh and Erin Weisbart and John Yong and Maria Lozada and Gregory P Way and Sanam L Kavari and Celeste Diaz and Marzieh Haghighi and Thiago M Batista and Joaquín Pérez-Schindler and Melina Claussnitzer and Shantanu Singh and Beth A Cimini and Paul C Blainey and Anne E Carpenter and Calvin H Jan and James T Neal},
doi = {10.1101/2023.08.06.552164},
year  = {2023},
date = {2023-08-01},
journal = {bioRxiv},
abstract = {A key challenge of the modern genomics era is developing data-driven representations of gene function. Here, we present the first unbiased morphology-based genome-wide perturbation atlas in human cells, containing three genome-scale genotype-phenotype maps comprising >20,000 single-gene CRISPR-Cas9-based knockout experiments in >30 million cells. Our optical pooled cell profiling approach (PERISCOPE) combines a de-stainable high-dimensional phenotyping panel (based on Cell Painting  ) with optical sequencing of molecular barcodes and a scalable open-source analysis pipeline to facilitate massively parallel screening of pooled perturbation libraries. This approach provides high-dimensional phenotypic profiles of individual cells, while simultaneously enabling interrogation of subcellular processes. Our atlas reconstructs known pathways and protein-protein interaction networks, identifies culture media-specific responses to gene knockout, and clusters thousands of human genes by phenotypic similarity. Using this atlas, we identify the poorly-characterized disease-associated transmembrane protein TMEM251/LYSET as a Golgi-resident protein essential for mannose-6-phosphate-dependent trafficking of lysosomal enzymes, showing the power of these representations. In sum, our atlas and screening technology represent a rich and accessible resource for connecting genes to cellular functions at scale.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37541189,
title = {HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder},
author = {Eva Niggl and Arjan Bouman and Lauren C Briere and Remco M Hoogenboezem and Ilse Wallaard and Joohyun Park and Jakob Admard and Martina Wilke and Emilio D R O Harris-Mostert and Minetta Elgersma and Jennifer Bain and Meena Balasubramanian and Siddharth Banka and Paul J Benke and Miriam Bertrand and Alyssa E Blesson and Jill Clayton-Smith and Jamie M Ellingford and Madelyn A Gillentine and Dana H Goodloe and Tobias B Haack and Mahim Jain and Ian Krantz and Sharon M Luu and Molly McPheron and Candace L Muss and Sarah E Raible and Nathaniel H Robin and Michael Spiller and Susan Starling and David A Sweetser and Isabelle Thiffault and Francesco Vetrini and Dennis Witt and Emily Woods and Dihong Zhou and  and  and Ype Elgersma and Annelot C M van Esbroeck},
doi = {10.1016/j.ajhg.2023.07.005},
issn = {1537-6605},
year  = {2023},
date = {2023-08-01},
journal = {Am J Hum Genet},
volume = {110},
number = {8},
pages = {1414--1435},
abstract = {Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37662408,
title = {Identification of a  mutation in  associated with a neurodevelopmental disorder and immunodeficiency},
author = {Marina Villamor-Payà and María Sanchiz-Calvo and Jordann Smak and Lynn Pais and Malika Sud and Uma Shankavaram and Alysia Kern Lovgren and Christina Austin-Tse and Vijay S Ganesh and Marina Gay and Marta Vilaseca and Gianluca Arauz-Garofalo and Lluís Palenzuela and Grace VanNoy and Anne O'Donnell-Luria and Travis H Stracker},
doi = {10.1101/2023.08.22.23294267},
year  = {2023},
date = {2023-08-01},
journal = {medRxiv},
abstract = {BACKGROUND: The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants are associated with 'Intellectual Disability, Autosomal Dominant 57' (MRD57), a neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown.nnMETHODS: A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a novel, heterozygous variant in TLK1 (c.1435C>G, p.Q479E) by genome sequencing (GS). Single cell gel electrophoresis, western blot, flow cytometry and RNA-seq were performed in patient-derived lymphoblast cell lines. In silico, biochemical and proteomic analysis were used to determine the functional impact of the p.Q479E variant and previously reported NDD-associated TLK1 variant, p.M566T.nnRESULTS: Transcriptome sequencing in patient-derived cells confirmed expression of TLK1 transcripts carrying the p.Q479E variant and revealed alterations in genes involved in class switch recombination and cytokine signaling. Cells expressing the p.Q479E variant exhibited reduced cytokine responses and higher levels of spontaneous DNA damage but not increased sensitivity to radiation or DNA repair defects. The p.Q479E and p.M566T variants impaired kinase activity but did not strongly alter localization or proximal protein interactions.nnCONCLUSION: Our study provides the first functional characterization of TLK1 variants associated with NDDs and suggests potential involvement in central nervous system and immune system development. Our results indicate that, like TLK2 variants, TLK1 variants may impact development in multiple tissues and should be considered in the diagnosis of rare NDDs.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37606250,
title = {Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in },
author = {Lucydalila Cedillo and Fasih M Ahsan and Sainan Li and Nicole L Stuhr and Yifei Zhou and Yuyao Zhang and Adebanjo Adedoja and Luke M Murphy and Armen Yerevanian and Sinclair Emans and Khoi Dao and Zhaozhi Li and Nicholas D Peterson and Jeramie Watrous and Mohit Jain and Sudeshna Das and Read Pukkila-Worley and Sean P Curran and Alexander A Soukas},
doi = {10.7554/eLife.82210},
issn = {2050-084X},
year  = {2023},
date = {2023-08-01},
journal = {Elife},
volume = {12},
abstract = {Biguanides, including the world's most prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. Despite this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in , we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor /Nrf. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, /FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37290968,
title = {Mechanistic Implications of Cortical Superficial Siderosis in Patients With Mixed Location Intracerebral Hemorrhage and Cerebral Microbleeds},
author = {Alvin S Das and Elif Gokcal and Alessandro Biffi and Robert W Regenhardt and Marco Pasi and Avia Abramovitz Fouks and Anand Viswanathan and Joshua Goldstein and Lee H Schwamm and Jonathan Rosand and Steven M Greenberg and M Edip Gurol},
doi = {10.1212/WNL.0000000000207476},
issn = {1526-632X},
year  = {2023},
date = {2023-08-01},
journal = {Neurology},
volume = {101},
number = {6},
pages = {e636--e644},
abstract = {BACKGROUND AND OBJECTIVES: Hypertensive cerebral small vessel disease (HTN-cSVD) is the predominant microangiopathy in patients with a combination of lobar and deep cerebral microbleeds (CMBs) and intracerebral hemorrhage (mixed ICH). We tested the hypothesis that cerebral amyloid angiopathy (CAA) is also a contributing microangiopathy in patients with mixed ICH with cortical superficial siderosis (cSS), a marker strongly associated with CAA.nnMETHODS: Brain MRIs from a prospective database of consecutive patients with nontraumatic ICH admitted to a referral center were reviewed for the presence of CMBs, cSS, and nonhemorrhagic CAA markers (lobar lacunes, centrum semiovale enlarged perivascular spaces [CSO-EPVS], and multispot white matter hyperintensity [WMH] pattern). The frequencies of CAA markers and left ventricular hypertrophy (LVH), a marker for hypertensive end-organ damage, were compared between patients with mixed ICH with cSS (mixed ICH/cSS[+]) and without cSS (mixed ICH/cSS[-]) in univariate and multivariable models.nnRESULTS: Of 1,791 patients with ICH, 40 had mixed ICH/cSS(+) and 256 had mixed ICH/cSS(-). LVH was less common in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-) (34% vs 59%,  = 0.01). The frequencies of CAA imaging markers, namely multispot pattern (18% vs 4%,  < 0.01) and severe CSO-EPVS (33% vs 11%,  < 0.01), were higher in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-). In a logistic regression model, older age (adjusted odds ratio [aOR] 1.04 per year, 95% CI 1.00-1.07,  = 0.04), lack of LVH (aOR 0.41, 95% CI 0.19-0.89,  = 0.02), multispot WMH pattern (aOR 5.25, 95% CI 1.63-16.94,  = 0.01), and severe CSO-EPVS (aOR 4.24, 95% CI 1.78-10.13,  < 0.01) were independently associated with mixed ICH/cSS(+) after further adjustment for hypertension and coronary artery disease. Among ICH survivors, the adjusted hazard ratio of ICH recurrence in patients with mixed ICH/cSS(+) was 4.65 (95% CI 1.38-11.38,  < 0.01) compared with that in patients with mixed ICH/cSS(-).nnDISCUSSION: The underlying microangiopathy of mixed ICH/cSS(+) likely includes both HTN-cSVD and CAA, whereas mixed ICH/cSS(-) is likely driven by HTN-cSVD. These imaging-based classifications can be important to stratify ICH risk but warrant confirmation in studies incorporating advanced imaging/pathology.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37561632,
title = {Tle4 controls both developmental acquisition and early post-natal maturation of corticothalamic projection neuron identity},
author = {Maria J Galazo and David A Sweetser and Jeffrey D Macklis},
doi = {10.1016/j.celrep.2023.112957},
issn = {2211-1247},
year  = {2023},
date = {2023-08-01},
journal = {Cell Rep},
volume = {42},
number = {8},
pages = {112957},
abstract = {Identities of distinct neuron subtypes are specified during embryonic development, then maintained during post-natal maturation. In cerebral cortex, mechanisms controlling early acquisition of neuron-subtype identities have become increasingly understood. However, mechanisms controlling neuron-subtype identity stability during post-natal maturation are largely unexplored. We identify that Tle4 is required for both early acquisition and post-natal stability of corticothalamic neuron-subtype identity. Embryonically, Tle4 promotes acquisition of corticothalamic identity and blocks emergence of core characteristics of subcerebral/corticospinal projection neuron identity, including gene expression and connectivity. During the first post-natal week, when corticothalamic innervation is ongoing, Tle4 is required to stabilize corticothalamic neuron identity, limiting interference from differentiation programs of developmentally related neuron classes. We identify a deacetylation-based epigenetic mechanism by which TLE4 controls Fezf2 expression level by corticothalamic neurons. This contributes to distinction of cortical output subtypes and ensures identity stability for appropriate maturation of corticothalamic neurons.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37555446,
title = {A Novel Home-Based Study of Circadian Rhythms: Design, Rationale, and Methods for the Circadia Study},
author = {Irma M Vlasac and Gregory W Bormes and Elizabeth Do and Selma S Benkhoukha and Naby Diallo and Noah L Fryou and Siena Gioia and Oluwaseun Akeju and Clarence Joseph and Anne Kuan and Jennifer Lapan and David Oluwadara and The Pepper Team and Shadab A Rahman and Richa Saxena and Frank A J L Scheer and M Brandon Westover and John W Winkelman and Faraji Woodson and Jacqueline M Lane},
doi = {10.1093/sleep/zsad197},
issn = {1550-9109},
year  = {2023},
date = {2023-08-01},
journal = {Sleep},
abstract = {The Circadia Study (Circadia) is a novel "direct-to-participant" research study investigating the genetics of circadian rhythm disorders of advanced and delayed sleep phase and non-24 hour rhythms. The goals of the Circadia Study are twofold: (i) to create an easy-to-use toolkit for at-home circadian phase assessment for patients with circadian rhythm disorders through the use of novel in-home based surveys, tests, and collection kits; and (ii) create a richly phenotyped patient resource for genetic studies that will lead to new genetic loci associated with circadian rhythm disorders revealing possible loci of interest to target in the development of therapeutics for circadian rhythm disorders. Through these goals, we aim to broaden our understanding and elucidate the genetics of circadian rhythm disorders across a diverse patient population while increasing accessibility to circadian rhythm disorder diagnostics reducing health disparities through self-directed at-home dim light melatonin onset (DLMO) collections.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36525397,
title = {Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)},
author = {Josephine H Li and James A Perry and Kathleen A Jablonski and Shylaja Srinivasan and Ling Chen and Jennifer N Todd and Maegan Harden and Josep M Mercader and Qing Pan and Adem Y Dawed and Sook Wah Yee and Ewan R Pearson and Kathleen M Giacomini and Ayush Giri and Adriana M Hung and Shujie Xiao and L Keoki Williams and Paul W Franks and Robert L Hanson and Steven E Kahn and William C Knowler and Toni I Pollin and Jose C Florez and },
doi = {10.2337/db22-0702},
issn = {1939-327X},
year  = {2023},
date = {2023-08-01},
journal = {Diabetes},
volume = {72},
number = {8},
pages = {1161--1172},
abstract = {Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes incidence. We identified four genome-wide significant variants after correcting for correlated traits (P < 9 × 10-9). In the MET arm, rs144322333 near ENOSF1 (minor allele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, β = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10-12). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, β = -7.55 [95% CI -9.88, -5.22]; P = 3.2 × 10-10) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 10-4]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37365732,
title = {Data Resource Profile: Nationwide registry data for high-throughput epidemiology and machine learning (FinRegistry)},
author = {Essi Viippola and Sara Kuitunen and Rodosthenis S Rodosthenous and Andrius Vabalas and Tuomo Hartonen and Pekka Vartiainen and Joanne Demmler and Anna-Leena Vuorinen and Aoxing Liu and Aki S Havulinna and Vincent Llorens and Kira E Detrois and Feiyi Wang and Matteo Ferro and Antti Karvanen and Jakob German and Sakari Jukarainen and Javier Gracia-Tabuenca and Tero Hiekkalinna and Sami Koskelainen and Tuomo Kiiskinen and Elisa Lahtela and Susanna Lemmelä and Teemu Paajanen and Harri Siirtola and Mary Pat Reeve and Kati Kristiansson and Minna Brunfeldt and Mervi Aavikko and Finn Gen and Markus Perola and Andrea Ganna and },
doi = {10.1093/ije/dyad091},
issn = {1464-3685},
year  = {2023},
date = {2023-08-01},
journal = {Int J Epidemiol},
volume = {52},
number = {4},
pages = {e195--e200},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37566429,
title = {Medicaid Enrollment and Service Use Among Adults With Down Syndrome},
author = {Eric Rubenstein and Amy Michals and Na Wang and Ashley Scott and Salina Tewolde and A Alex Levine and Yorghos Tripodis and Brian G Skotko},
doi = {10.1001/jamahealthforum.2023.2320},
issn = {2689-0186},
year  = {2023},
date = {2023-08-01},
journal = {JAMA Health Forum},
volume = {4},
number = {8},
pages = {e232320},
abstract = {IMPORTANCE: Down syndrome is the leading genetic cause of intellectual disability and automatically qualifies individuals for Social Security Insurance. Therefore, Medicaid is the major health insurance provider for a population at high risk for dementia, obesity, and premature mortality. Despite the importance of Medicaid for adults with Down syndrome, little is known about how this population uses Medicaid.nnOBJECTIVE: To describe enrollment in, health care use in, and cost to Medicaid for adults with Down syndrome compared with adults with intellectual disability and a random sample of adults enrolled in Medicaid.nnDESIGN, SETTING, AND PARTICIPANTS: In this cohort study, the data are from a claims cohort of adults aged 18 years or older enrolled in Medicaid at any point between January 1, 2011, and December 31, 2019. Participants were enrollees with 1 or more inpatient claim or 2 or more other claims with an International Classification of Diseases, Ninth Revision code or an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code for Down syndrome or intellectual disability as well as a random sample of those without developmental disability. Analyses were conducted from June 2022 to February 2023.nnMAIN OUTCOMES AND MEASURES: Data were linked across 2 data reporting systems. Main outcomes were enrollee demographic characteristics, enrollment characteristics, cost, and service use.nnRESULTS: This cohort study included 123 024 individuals with Down syndrome (820 273 person-years of coverage; mean [SD] age, 35 [14.7] years; median age, 33 years [IQR, 21-48 years]; 51.6% men; 14.1% Black individuals; 16.7% Hispanic individuals; and 74.6% White individuals), 1 182 246 individuals with intellectual disability (mean [SD] age, 37.1 [16.8] years; median age, 33 years [IQR, 22-50 years]; 56.5% men; 22.0% Black individuals; 11.7% Hispanic individuals; and 69.5% White individuals), and 3 176 371 individuals with no developmental disabilities (mean [SD] age, 38 [18.6] years; median age, 33 years [IQR, 21-52 years]; 43.8% men; 23.7% Black individuals; 20.7% Hispanic individuals; and 61.3% White individuals). Median enrollment in Medicaid for a person with Down syndrome was 8.0 years (IQR, 5.0-9.0 years; mean [SD], 6.6 [2.6] years). Costs were higher for the Down syndrome group (median, $26 278 per person-year [IQR, $11 145-$55 928 per person-year]) relative to the group with no developmental disabilities (median, $6173 per person-year [IQR, $868-$58 390 per person-year]). Asian, Black, Hispanic, Native American, and Pacific Islander adults with Down syndrome had fewer costs and claims per person-year compared with White adults with Down syndrome.nnCONCLUSION AND RELEVANCE: This cohort study of individuals with Down syndrome enrolled in Medicaid found consistent enrollment and high use of health care in a population with high health care needs. Results were similar comparing individuals with Down syndrome and those with intellectual disability, with both groups differing from a sample of Medicaid enrollees with no developmental disabilities. Medicaid data are a useful tool for understanding the health and well-being of individuals with Down syndrome.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37582836,
title = {Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo},
author = {Yong Tao and Veronica Lamas and Wan Du and Wenliang Zhu and Yiran Li and Madelynn N Whittaker and John A Zuris and David B Thompson and Arun Prabhu Rameshbabu and Yilai Shu and Xue Gao and Johnny H Hu and Charles Pei and Wei-Jia Kong and Xuezhong Liu and Hao Wu and Benjamin P Kleinstiver and David R Liu and Zheng-Yi Chen},
doi = {10.1038/s41467-023-40476-7},
issn = {2041-1723},
year  = {2023},
date = {2023-08-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {4928},
abstract = {Mutations in Atp2b2, an outer hair cell gene, cause dominant hearing loss in humans. Using a mouse model Atp2b2, with a dominant hearing loss mutation (Oblivion), we show that liposome-mediated in vivo delivery of CRISPR-Cas9 ribonucleoprotein complexes leads to specific editing of the Obl allele. Large deletions encompassing the Obl locus and indels were identified as the result of editing. In vivo genome editing promotes outer hair cell survival and restores their function, leading to hearing recovery. We further show that in a double-dominant mutant mouse model, in which the Tmc1 Beethoven mutation and the Atp2b2 Oblivion mutation cause digenic genetic hearing loss, Cas9/sgRNA delivery targeting both mutations leads to partial hearing recovery. These findings suggest that liposome-RNP delivery can be used as a strategy to recover hearing with dominant mutations in OHC genes and with digenic mutations in the auditory hair cells, potentially expanding therapeutics of gene editing to treat hearing loss.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37587338,
title = {Nuclear genetic control of mtDNA copy number and heteroplasmy in humans},
author = {Rahul Gupta and Masahiro Kanai and Timothy J Durham and Kristin Tsuo and Jason G McCoy and Anna V Kotrys and Wei Zhou and Patrick F Chinnery and Konrad J Karczewski and Sarah E Calvo and Benjamin M Neale and Vamsi K Mootha},
doi = {10.1038/s41586-023-06426-5},
issn = {1476-4687},
year  = {2023},
date = {2023-08-01},
journal = {Nature},
volume = {620},
number = {7975},
pages = {839--848},
abstract = {Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation. Heteroplasmy refers to the presence of a mixture of mtDNA alleles in an individual and has been associated with disease and ageing. Mechanisms underlying common variation in human heteroplasmy, and the influence of the nuclear genome on this variation, remain insufficiently explored. Here we quantify mtDNA copy number (mtCN) and heteroplasmy using blood-derived whole-genome sequences from 274,832 individuals and perform genome-wide association studies to identify associated nuclear loci. Following blood cell composition correction, we find that mtCN declines linearly with age and is associated with variants at 92 nuclear loci. We observe that nearly everyone harbours heteroplasmic mtDNA variants obeying two principles: (1) heteroplasmic single nucleotide variants tend to arise somatically and accumulate sharply after the age of 70 years, whereas (2) heteroplasmic indels are maternally inherited as mixtures with relative levels associated with 42 nuclear loci involved in mtDNA replication, maintenance and novel pathways. These loci may act by conferring a replicative advantage to certain mtDNA alleles. As an illustrative example, we identify a length variant carried by more than 50% of humans at position chrM:302 within a G-quadruplex previously proposed to mediate mtDNA transcription/replication switching. We find that this variant exerts cis-acting genetic control over mtDNA abundance and is itself associated in-trans with nuclear loci encoding machinery for this regulatory switch. Our study suggests that common variation in the nuclear genome can shape variation in mtCN and heteroplasmy dynamics across the human population.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37443254,
title = {Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases},
author = {Elle M Weeks and Jacob C Ulirsch and Nathan Y Cheng and Brian L Trippe and Rebecca S Fine and Jenkai Miao and Tejal A Patwardhan and Masahiro Kanai and Joseph Nasser and Charles P Fulco and Katherine C Tashman and Francois Aguet and Taibo Li and Jose Ordovas-Montanes and Christopher S Smillie and Moshe Biton and Alex K Shalek and Ashwin N Ananthakrishnan and Ramnik J Xavier and Aviv Regev and Rajat M Gupta and Kasper Lage and Kristin G Ardlie and Joel N Hirschhorn and Eric S Lander and Jesse M Engreitz and Hilary K Finucane},
doi = {10.1038/s41588-023-01443-6},
issn = {1546-1718},
year  = {2023},
date = {2023-08-01},
journal = {Nat Genet},
volume = {55},
number = {8},
pages = {1267--1276},
abstract = {Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37278238,
title = {Genetic Susceptibility to Atrial Fibrillation Identified via Deep Learning of 12-Lead Electrocardiograms},
author = {Xin Wang and Shaan Khurshid and Seung Hoan Choi and Samuel Friedman and Lu-Chen Weng and Christopher Reeder and James P Pirruccello and Pulkit Singh and Emily S Lau and Rachael Venn and Nate Diamant and Paolo Di Achille and Anthony Philippakis and Christopher D Anderson and Jennifer E Ho and Patrick T Ellinor and Puneet Batra and Steven A Lubitz},
doi = {10.1161/CIRCGEN.122.003808},
issn = {2574-8300},
year  = {2023},
date = {2023-08-01},
journal = {Circ Genom Precis Med},
volume = {16},
number = {4},
pages = {340--349},
abstract = {BACKGROUND: Artificial intelligence (AI) models applied to 12-lead ECG waveforms can predict atrial fibrillation (AF), a heritable and morbid arrhythmia. However, the factors forming the basis of risk predictions from AI models are usually not well understood. We hypothesized that there might be a genetic basis for an AI algorithm for predicting the 5-year risk of new-onset AF using 12-lead ECGs (ECG-AI)-based risk estimates.nnMETHODS: We applied a validated ECG-AI model for predicting incident AF to ECGs from 39 986 UK Biobank participants without AF. We then performed a genome-wide association study (GWAS) of the predicted AF risk and compared it with an AF GWAS and a GWAS of risk estimates from a clinical variable model.nnRESULTS: In the ECG-AI GWAS, we identified 3 signals (<5×10) at established AF susceptibility loci marked by the sarcomeric gene  and sodium channel genes  and . We also identified 2 novel loci near the genes  and . In contrast, the clinical variable model prediction GWAS indicated a different genetic profile. In genetic correlation analysis, the prediction from the ECG-AI model was estimated to have a higher correlation with AF than that from the clinical variable model.nnCONCLUSIONS: Predicted AF risk from an ECG-AI model is influenced by genetic variation implicating sarcomeric, ion channel and body height pathways. ECG-AI models may identify individuals at risk for disease via specific biological pathways.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37353344,
title = {Type 2 Diabetes Polygenic Score Predicts the Risk of Glucocorticoid-Induced Hyperglycemia in Patients Without Diabetes},
author = {Aaron J Deutsch and Philip H Schroeder and Ravi Mandla and Sarah Kang and Feyza Erenler and Josep M Mercader and Miriam S Udler and Jose C Florez and Laura N Brenner},
doi = {10.2337/dc23-0353},
issn = {1935-5548},
year  = {2023},
date = {2023-08-01},
journal = {Diabetes Care},
volume = {46},
number = {8},
pages = {1541--1545},
abstract = {OBJECTIVE: To assess whether increased genetic risk of type 2 diabetes (T2D) is associated with the development of hyperglycemia after glucocorticoid treatment.nnRESEARCH DESIGN AND METHODS: We performed a retrospective analysis of individuals with no diagnosis of diabetes who received a glucocorticoid dose of ≥10 mg prednisone. We analyzed the association between hyperglycemia and a T2D global extended polygenic score, which was constructed through a meta-analysis of two published genome-wide association studies.nnRESULTS: Of 546 individuals who received glucocorticoids, 210 developed hyperglycemia and 336 did not. T2D polygenic score was significantly associated with glucocorticoid-induced hyperglycemia (odds ratio 1.4 per SD of polygenic score; P = 0.038).nnCONCLUSIONS: Individuals with increased genetic risk of T2D have a higher risk of glucocorticoid-induced hyperglycemia. This finding offers a mechanism for risk stratification as part of a precision approach to medical treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37543680,
title = {Multi-PGS enhances polygenic prediction by combining 937 polygenic scores},
author = {Clara Albiñana and Zhihong Zhu and Andrew J Schork and Andrés Ingason and Hugues Aschard and Isabell Brikell and Cynthia M Bulik and Liselotte V Petersen and Esben Agerbo and Jakob Grove and Merete Nordentoft and David M Hougaard and Thomas Werge and Anders D Børglum and Preben Bo Mortensen and John J McGrath and Benjamin M Neale and Florian Privé and Bjarni J Vilhjálmsson},
doi = {10.1038/s41467-023-40330-w},
issn = {2041-1723},
year  = {2023},
date = {2023-08-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {4702},
abstract = {The predictive performance of polygenic scores (PGS) is largely dependent on the number of samples available to train the PGS. Increasing the sample size for a specific phenotype is expensive and takes time, but this sample size can be effectively increased by using genetically correlated phenotypes. We propose a framework to generate multi-PGS from thousands of publicly available genome-wide association studies (GWAS) with no need to individually select the most relevant ones. In this study, the multi-PGS framework increases prediction accuracy over single PGS for all included psychiatric disorders and other available outcomes, with prediction R increases of up to 9-fold for attention-deficit/hyperactivity disorder compared to a single PGS. We also generate multi-PGS for phenotypes without an existing GWAS and for case-case predictions. We benchmark the multi-PGS framework against other methods and highlight its potential application to new emerging biobanks.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36916878,
title = {Impaired Adipocyte SLC7A10 Promotes Lipid Storage in Association With Insulin Resistance and Altered BCAA Metabolism},
author = {Regine Å Jersin and Divya Sri Priyanka Tallapragada and Linn Skartveit and Mona S Bjune and Maheswary Muniandy and Sindre Lee-Ødegård and Sini Heinonen and Marcus Alvarez and Kåre Inge Birkeland and Christian André Drevon and Päivi Pajukanta and Adrian McCann and Kirsi H Pietiläinen and Melina Claussnitzer and Gunnar Mellgren and Simon N Dankel},
doi = {10.1210/clinem/dgad148},
issn = {1945-7197},
year  = {2023},
date = {2023-08-01},
journal = {J Clin Endocrinol Metab},
volume = {108},
number = {9},
pages = {2217--2229},
abstract = {CONTEXT: The neutral amino acid transporter SLC7A10/ASC-1 is an adipocyte-expressed gene with reduced expression in insulin resistance and obesity. Inhibition of SLC7A10 in adipocytes was shown to increase lipid accumulation despite decreasing insulin-stimulated uptake of glucose, a key substrate for de novo lipogenesis. These data imply that alternative lipogenic substrates to glucose fuel continued lipid accumulation during insulin resistance in obesity.nnOBJECTIVE: We examined whether increased lipid accumulation during insulin resistance in adipocytes may involve alter flux of lipogenic amino acids dependent on SLC7A10 expression and activity, and whether this is reflected by extracellular and circulating concentrations of marker metabolites.nnMETHODS: In adipocyte cultures with impaired SLC7A10, we performed RNA sequencing and relevant functional assays. By targeted metabolite analyses (GC-MS/MS), flux of all amino acids and selected metabolites were measured in human and mouse adipose cultures. Additionally, SLC7A10 mRNA levels in human subcutaneous adipose tissue (SAT) were correlated to candidate metabolites and adiposity phenotypes in 2 independent cohorts.nnRESULTS: SLC7A10 impairment altered expression of genes related to metabolic processes, including branched-chain amino acid (BCAA) catabolism, lipogenesis, and glyceroneogenesis. In 3T3-L1 adipocytes, SLC7A10 inhibition increased fatty acid uptake and cellular content of glycerol and cholesterol. SLC7A10 impairment in SAT cultures altered uptake of aspartate and glutamate, and increased net uptake of BCAAs, while increasing the net release of the valine catabolite 3- hydroxyisobutyrate (3-HIB). In human cohorts, SLC7A10 mRNA correlated inversely with total fat mass, circulating triacylglycerols, BCAAs, and 3-HIB.nnCONCLUSION: Reduced SLC7A10 activity strongly affects flux of BCAAs in adipocytes, which may fuel continued lipogenesis during insulin resistance, and be reflected in increased circulating levels of the valine-derived catabolite 3-HIB.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37543292,
title = {MicroRNA biomarkers target genes and pathways associated with type 2 diabetes},
author = {Dorian Kariuki and Bradley E Aouizerat and Kesava Asam and Alka M Kanaya and Li Zhang and Jose C Florez and Elena Flowers},
doi = {10.1016/j.diabres.2023.110868},
issn = {1872-8227},
year  = {2023},
date = {2023-08-01},
journal = {Diabetes Res Clin Pract},
volume = {203},
pages = {110868},
abstract = {AIMS/HYPOTHESIS: Our prior analysis of the Diabetes Prevention Program study identified a subset of five miRNAs that predict incident type 2 diabetes. The purpose of this study was to identify mRNAs and biological pathways targeted by these five miRNAs to elucidate potential mechanisms of risk and responses to the tested interventions.nnMETHODS: Using experimentally validated data from miRTarBase version 8.0 and R (2021), we identified mRNAs with strong evidence to be regulated by individual or combinations of the five predictor miRNAs. Overrepresentation of the mRNA targets was assessed in pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation database.nnRESULTS: The five miRNAs targeted 167 pathways and 122 mRNAs. Nine of the pathways have known associations with type 2 diabetes: Insulin signaling, Insulin resistance, Diabetic cardiomyopathy, Type 2 diabetes, AGE-RAGE signaling in diabetic complications, HIF-1 signaling, TGF-beta signaling, PI3K/Akt signaling, and Adipocytokine signaling pathways. Vascular endothelial growth factor A (VEGFA) has prior genetic associations with risk for type 2 diabetes and was the most commonly targeted mRNA for this set of miRNAs.nnCONCLUSIONS/INTERPRETATION: These findings show that miRNA predictors of incident type 2 diabetes target mRNAs and pathways known to underlie risk for type 2 diabetes. Future studies should evaluate miRNAs as potential therapeutic targets for preventing and treating type 2 diabetes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37577678,
title = {Critical assessment of variant prioritization methods for rare disease diagnosis within the Rare Genomes Project},
author = {Sarah L Stenton and Melanie O'Leary and Gabrielle Lemire and Grace E VanNoy and Stephanie DiTroia and Vijay S Ganesh and Emily Groopman and Emily O'Heir and Brian Mangilog and Ikeoluwa Osei-Owusu and Lynn S Pais and Jillian Serrano and Moriel Singer-Berk and Ben Weisburd and Michael Wilson and Christina Austin-Tse and Marwa Abdelhakim and Azza Althagafi and Giulia Babbi and Riccardo Bellazzi and Samuele Bovo and Maria Giulia Carta and Rita Casadio and Pieter-Jan Coenen and Federica De Paoli and Matteo Floris and Manavalan Gajapathy and Robert Hoehndorf and Julius O B Jacobsen and Thomas Joseph and Akash Kamandula and Panagiotis Katsonis and Cyrielle Kint and Olivier Lichtarge and Ivan Limongelli and Yulan Lu and Paolo Magni and Tarun Karthik Kumar Mamidi and Pier Luigi Martelli and Marta Mulargia and Giovanna Nicora and Keith Nykamp and Vikas Pejaver and Yisu Peng and Thi Hong Cam Pham and Maurizio S Podda and Aditya Rao and Ettore Rizzo and Vangala G Saipradeep and Castrense Savojardo and Peter Schols and Yang Shen and Naveen Sivadasan and Damian Smedley and Dorian Soru and Rajgopal Srinivasan and Yuanfei Sun and Uma Sunderam and Wuwei Tan and Naina Tiwari and Xiao Wang and Yaqiong Wang and Amanda Williams and Elizabeth A Worthey and Rujie Yin and Yuning You and Daniel Zeiberg and Susanna Zucca and Constantina Bakolitsa and Steven E Brenner and Stephanie M Fullerton and Predrag Radivojac and Heidi L Rehm and Anne O'Donnell-Luria},
doi = {10.1101/2023.08.02.23293212},
year  = {2023},
date = {2023-08-01},
journal = {medRxiv},
abstract = {BACKGROUND: A major obstacle faced by rare disease families is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years, and causal variants are identified in under 50%. The Rare Genomes Project (RGP) is a direct-to-participant research study on the utility of genome sequencing (GS) for diagnosis and gene discovery. Families are consented for sharing of sequence and phenotype data with researchers, allowing development of a Critical Assessment of Genome Interpretation (CAGI) community challenge, placing variant prioritization models head-to-head in a real-life clinical diagnostic setting.nnMETHODS: Predictors were provided a dataset of phenotype terms and variant calls from GS of 175 RGP individuals (65 families), including 35 solved training set families, with causal variants specified, and 30 test set families (14 solved, 16 unsolved). The challenge tasked teams with identifying the causal variants in as many test set families as possible. Ranked variant predictions were submitted with estimated probability of causal relationship (EPCR) values. Model performance was determined by two metrics, a weighted score based on rank position of true positive causal variants and maximum F-measure, based on precision and recall of causal variants across EPCR thresholds.nnRESULTS: Sixteen teams submitted predictions from 52 models, some with manual review incorporated. Top performing teams recalled the causal variants in up to 13 of 14 solved families by prioritizing high quality variant calls that were rare, predicted deleterious, segregating correctly, and consistent with reported phenotype. In unsolved families, newly discovered diagnostic variants were returned to two families following confirmatory RNA sequencing, and two prioritized novel disease gene candidates were entered into Matchmaker Exchange. In one example, RNA sequencing demonstrated aberrant splicing due to a deep intronic indel in  , identified in  with a frameshift variant, in an unsolved proband with phenotype overlap with asparagine synthetase deficiency.nnCONCLUSIONS: By objective assessment of variant predictions, we provide insights into current state-of-the-art algorithms and platforms for genome sequencing analysis for rare disease diagnosis and explore areas for future optimization. Identification of diagnostic variants in unsolved families promotes synergy between researchers with clinical and computational expertise as a means of advancing the field of clinical genome interpretation.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37460667,
title = {Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions},
author = {Paolo Bernardi and Christoph Gerle and Andrew P Halestrap and Elizabeth A Jonas and Jason Karch and Nelli Mnatsakanyan and Evgeny Pavlov and Shey-Shing Sheu and Alexander A Soukas},
doi = {10.1038/s41418-023-01187-0},
issn = {1476-5403},
year  = {2023},
date = {2023-08-01},
journal = {Cell Death Differ},
volume = {30},
number = {8},
pages = {1869--1885},
abstract = {The mitochondrial permeability transition (mPT) describes a Ca-dependent and cyclophilin D (CypD)-facilitated increase of inner mitochondrial membrane permeability that allows diffusion of molecules up to 1.5 kDa in size. It is mediated by a non-selective channel, the mitochondrial permeability transition pore (mPTP). Sustained mPTP opening causes mitochondrial swelling, which ruptures the outer mitochondrial membrane leading to subsequent apoptotic and necrotic cell death, and is implicated in a range of pathologies. However, transient mPTP opening at various sub-conductance states may contribute several physiological roles such as alterations in mitochondrial bioenergetics and rapid Ca efflux. Since its discovery decades ago, intensive efforts have been made to identify the exact pore-forming structure of the mPT. Both the adenine nucleotide translocase (ANT) and, more recently, the mitochondrial FF (F)-ATP synthase dimers, monomers or c-subunit ring alone have been implicated. Here we share the insights of several key investigators with different perspectives who have pioneered mPT research. We critically assess proposed models for the molecular identity of the mPTP and the mechanisms underlying its opposing roles in the life and death of cells. We provide in-depth insights into current controversies, seeking to achieve a degree of consensus that will stimulate future innovative research into the nature and role of the mPTP.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37409780,
title = {Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study},
author = {Thomas O Crawford and Kathryn J Swoboda and Darryl C De Vivo and Enrico Bertini and Wuh-Liang Hwu and Richard S Finkel and Janbernd Kirschner and Nancy L Kuntz and Aledie Navas Nazario and Julie A Parsons and Astrid Pechmann and Monique M Ryan and Russell J Butterfield and Haluk Topaloglu and Tawfeg Ben-Omran and Valeria A Sansone and Yuh-Jyh Jong and Francy Shu and Cong Zhu and Stephanie Raynaud and Tiffany R Lago and Angela D Paradis and Richard Foster and Russell Chin and Zdenek Berger and },
doi = {10.1002/mus.27853},
issn = {1097-4598},
year  = {2023},
date = {2023-08-01},
journal = {Muscle Nerve},
volume = {68},
number = {2},
pages = {157--170},
abstract = {INTRODUCTION/AIMS: NURTURE (NCT02386553) is an open-label study of nusinersen in children (two SMN2 copies, n = 15; three SMN2 copies, n = 10) who initiated treatment in the presymptomatic stage of spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 y of follow-up (data cut: February 15, 2021) are reported.nnMETHODS: The primary endpoint is time to death or respiratory intervention (≥6 h/day continuously for ≥7 days or tracheostomy). Secondary outcomes include overall survival, motor function, and safety.nnRESULTS: Median age of children was 4.9 (3.8-5.5) y at last visit. No children have discontinued the study or treatment. All were alive. No additional children utilized respiratory intervention (defined per primary endpoint) since the prior data cut. Children with three SMN2 copies achieved all World Health Organization (WHO) motor milestones, with all but one milestone in one child within normal developmental timeframes. All 15 children with two SMN2 copies achieved sitting without support, 14/15 walking with assistance, and 13/15 walking alone. Mean Hammersmith Functional Motor Scale Expanded total scores showed continued improvement. Subgroups with two SMN2 copies, minimum baseline compound muscle action potential amplitude ≥2 mV, and no baseline areflexia had better motor and nonmotor outcomes versus all children with two SMN2 copies.nnDISCUSSION: These results demonstrate the value of early treatment, durability of treatment effect, and favorable safety profile after ~5 y of nusinersen treatment. Inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37610752,
title = {Trimethylamine N-Oxide and White Matter Hyperintensity Volume Among Patients With Acute Ischemic Stroke},
author = {Naruchorn Kijpaisalratana and Zsuzsanna Ament and Matthew B Bevers and Varun M Bhave and Ana-Lucia Garcia Guarniz and Catharine A Couch and M Ryan Irvin and W Taylor Kimberly},
doi = {10.1001/jamanetworkopen.2023.30446},
issn = {2574-3805},
year  = {2023},
date = {2023-08-01},
journal = {JAMA Netw Open},
volume = {6},
number = {8},
pages = {e2330446},
abstract = {IMPORTANCE: Although increasing evidence suggests that trimethylamine N-oxide (TMAO) is associated with atherosclerosis, little is known about whether TMAO and its related metabolites (ie, choline, betaine, and carnitine) are associated with small vessel disease.nnOBJECTIVE: To evaluate the association between TMAO and its related metabolites with features of cerebral small vessel disease, including white matter hyperintensity volume (WMHV) and acute lacunar infarction.nnDESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included patients enrolled in the Specialized Programs of Translational Research in Acute Stroke biorepository. The registry included 522 patients with acute ischemic stroke who were 18 years or older who presented at the Massachusetts General Hospital or Brigham and Women's Hospital within 9 hours after onset between January 2007 and April 2010. The analyses in this study were conducted between November 2022 and April 2023.nnEXPOSURES: Plasma TMAO, choline, betaine, and carnitine were measured by liquid chromatography-tandem mass spectrometry.nnMAIN OUTCOMES AND MEASURES: WMHV was quantified by a semiautomated approach using signal intensity threshold with subsequent manual editing. Ischemic stroke subtype was classified using the Causative Classification System.nnRESULTS: Among 351 patients included in this study, the mean (SD) age was 69 (15) years; 209 patients (59.5%) were male and had a median (IQR) admission National Institute of Health Stroke Scale of 6 (3-13). The magnetic resonance imaging subgroup consisted of 291 patients with a mean (SD) age of 67 (15) years. Among these, the median (IQR) WMHV was 3.2 (1.31-8.4) cm3. TMAO was associated with WMHV after adjustment for age and sex (β, 0.15; 95% CI, 0.01-0.29; P < .001). TMAO remained significant in a multivariate analysis adjusted for age, sex, hypertension, diabetes, and smoking (β, 0.14; 95% CI, 0-0.29; P = .05). TMAO was associated with lacunar stroke but not other ischemic stroke subtypes in a model adjusted for age, sex, hypertension, diabetes, and smoking (OR, 1.67; 95% CI, 1.05-2.66; P = .03).nnCONCLUSIONS AND RELEVANCE: In this observational study, TMAO was associated with cerebral small vessel disease determined by WMHV and acute lacunar infarction. The association was independent of traditional vascular risk factors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37376759,
title = {An Engineered Adeno-Associated Virus Capsid Mediates Efficient Transduction of Pericytes and Smooth Muscle Cells of the Brain Vasculature},
author = {Servio H Ramirez and Jonathan F Hale and Siobhan McCarthy and Christian L Cardenas and Kalpani N Udeni Galpayage Dona and Killian S Hanlon and Eloise Hudry and Demitri De La Cruz and Carrie Ng and Sabyasachi Das and Diane M Nguyen and Josette Nammour and Rachel E Bennett and Allison M Andrews and Patricia L Musolino and Casey A Maguire},
doi = {10.1089/hum.2022.211},
issn = {1557-7422},
year  = {2023},
date = {2023-08-01},
journal = {Hum Gene Ther},
volume = {34},
number = {15-16},
pages = {682--696},
abstract = {Neurodegeneration and cerebrovascular disease share an underlying microvascular dysfunction that may be remedied by selective transgene delivery. To date, limited options exist in which cellular components of the brain vasculature can be effectively targeted by viral vector therapeutics. In this study, we characterize the first engineered adeno-associated virus (AAV) capsid mediating high transduction of cerebral vascular pericytes and smooth muscle cells (SMCs). We performed two rounds of  selection with an AAV capsid scaffold displaying a heptamer peptide library to isolate capsids that traffic to the brain after intravenous delivery. One identified capsid, termed AAV-PR, demonstrated high transduction of the brain vasculature, in contrast to the parental capsid, AAV9, which transduces mainly neurons and astrocytes. Further analysis using tissue clearing, volumetric rendering, and colocalization revealed that AAV-PR enabled high transduction of cerebral pericytes located on small-caliber vessels and SMCs in the larger arterioles and penetrating pial arteries. Analysis of tissues in the periphery indicated that AAV-PR also transduced SMCs in large vessels associated with the systemic vasculature. AAV-PR was also able to transduce primary human brain pericytes with higher efficiency than AAV9. Compared with previously published AAV capsids tropisms, AAV-PR represents the first capsid to allow for effective transduction of brain pericytes and SMCs and offers the possibility of genetically modulating these cell types in the context of neurodegeneration and other neurological diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37601974,
title = {Multi-ancestry meta-analysis identifies 5 novel loci for ischemic stroke and reveals heterogeneity of effects between sexes and ancestries},
author = {Ida Surakka and Kuan-Han Wu and Whitney Hornsby and Brooke N Wolford and Fred Shen and Wei Zhou and Jennifer E Huffman and Anita Pandit and Yao Hu and Ben Brumpton and Anne Heidi Skogholt and Maiken E Gabrielsen and Robin G Walters and  and  and Kristian Hveem and Charles Kooperberg and Sebastian Zöllner and Peter W F Wilson and Nadia R Sutton and Mark J Daly and Benjamin M Neale and Cristen J Willer and },
doi = {10.1016/j.xgen.2023.100345},
issn = {2666-979X},
year  = {2023},
date = {2023-08-01},
journal = {Cell Genom},
volume = {3},
number = {8},
pages = {100345},
abstract = {Stroke is the second leading cause of death and disability worldwide. Stroke prevalence varies by sex and ancestry, possibly due to genetic heterogeneity between subgroups. We performed a genome-wide meta-analysis of 16 biobanks across multiple ancestries to study the genetics of ischemic stroke (60,176 cases, 1,310,725 controls) as part of the Global Biobank Meta-analysis Initiative (GBMI) and further combined the results with previously published MegaStroke. Five novel loci for ischemic stroke (, , , , and ) were identified after replication in four additional datasets. One previously reported locus showed significant ancestry heterogeneity (), and one showed significant sex heterogeneity (). The  association was male specific (males p = 1.67e-24, females p = 0.126) and was additionally observed only in the East Asian ancestry (male) samples. These findings emphasize the need for more diverse datasets with large sample sizes to further understand the genetic predisposition of stroke in different ancestry and sex groups.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37262067,
title = {Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma},
author = {Raj K Gopal and Venkata R Vantaku and Apekshya Panda and Bryn Reimer and Sneha Rath and Tsz-Leung To and Adam S Fisch and Murat Cetinbas and Maia Livneh and Michael J Calcaterra and Benjamin J Gigliotti and Kerry A Pierce and Clary B Clish and Dora Dias-Santagata and Peter M Sadow and Lori J Wirth and Gilbert H Daniels and Ruslan I Sadreyev and Sarah E Calvo and Sareh Parangi and Vamsi K Mootha},
doi = {10.1158/2159-8290.CD-22-0976},
issn = {2159-8290},
year  = {2023},
date = {2023-08-01},
journal = {Cancer Discov},
volume = {13},
number = {8},
pages = {1904--1921},
abstract = {Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA sequencing and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity.nnSIGNIFICANCE: HCC harbors abundant mitochondria, mitochondrial DNA mutations, and chromosomal losses. Using a CRISPR-Cas9 screen inspired by transcriptomic and metabolomic profiling, we identify molecular effectors essential for cell fitness. We uncover lipid peroxide stress as a vulnerability coupled to mitochondrial complex I loss in HCC. See related article by Frank et al., p. 1884. This article is highlighted in the In This Issue feature, p. 1749.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37451268,
title = {De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling},
author = {Manuela Morleo and Rossella Venditti and Evangelos Theodorou and Lauren C Briere and Marion Rosello and Alfonsina Tirozzi and Roberta Tammaro and Nour Al-Badri and Frances A High and Jiahai Shi and  and  and Elena Putti and Luigi Ferrante and Viviana Cetrangolo and Annalaura Torella and Melissa A Walker and Romano Tenconi and Maria Iascone and Davide Mei and Renzo Guerrini and Jasper van der Smagt and Hester Y Kroes and Koen L I van Gassen and Muhammad Bilal and Muhammad Umair and Veronica Pingault and Tania Attie-Bitach and Jeannine Amiel and Resham Ejaz and Lance Rodan and Marcella Zollino and Pankaj B Agrawal and Filippo Del Bene and Vincenzo Nigro and David A Sweetser and Brunella Franco},
doi = {10.1016/j.ajhg.2023.06.012},
issn = {1537-6605},
year  = {2023},
date = {2023-08-01},
journal = {Am J Hum Genet},
volume = {110},
number = {8},
pages = {1377--1393},
abstract = {Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37532519,
title = {ZSWIM8 destabilizes many murine microRNAs and is required for proper embryonic growth and development},
author = {Charlie Y Shi and Lara E Elcavage and Raghu R Chivukula and Joanna Stefano and Benjamin Kleaveland and David P Bartel},
doi = {10.1101/gr.278073.123},
issn = {1549-5469},
year  = {2023},
date = {2023-08-01},
journal = {Genome Res},
abstract = {MicroRNAs (miRNAs) pair to sites in mRNAs to direct the degradation of these RNA transcripts. Conversely, certain RNA transcripts can direct the degradation of particular miRNAs. This target-directed miRNA degradation (TDMD) requires the ZSWIM8 E3 ubiquitin ligase. Here, we report the function of ZSWIM8 in the mouse embryo.   embryos were smaller than their littermates and died near the time of birth. This highly penetrant perinatal lethality was apparently caused by a lung sacculation defect attributed to failed maturation of alveolar epithelial cells. Some mutant individuals also had heart ventricular septal defects. These developmental abnormalities were accompanied by aberrant accumulation of more than 50 miRNAs observed across 12 tissues, which often led to enhanced repression of their mRNA targets. These ZSWIM8-sensitive miRNAs were preferentially produced from genomic miRNA clusters, and in some cases, ZSWIM8 caused a switch in the dominant strand or isoform that accumulated from a miRNA hairpin-observations suggesting that TDMD provides a mechanism to uncouple coproduced miRNAs from each other. Overall, our findings indicate that the regulatory influence of ZSWIM8, and presumably TDMD, in mammalian biology is widespread and consequential, and posit the existence of many yet-unidentified transcripts that trigger miRNA degradation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37183579,
title = {Global health measures from a National Down Syndrome Registry},
author = {Stephanie L Santoro and Kelsey Haugen and Karen Donelan and Brian G Skotko},
doi = {10.1002/ajmg.a.63243},
issn = {1552-4833},
year  = {2023},
date = {2023-08-01},
journal = {Am J Med Genet A},
volume = {191},
number = {8},
pages = {2092--2099},
abstract = {People with Down syndrome (DS) have a unique medical profile which may impact views of health. We aimed to study the use of global health measures for DS in a national cohort. We prospectively surveyed parents of individuals with DS from the DS-Connect® registry with validated Patient Reported Outcomes Measurement Information System (PROMIS)® instruments of global health. Analyses included use of scoring manuals and the PROMIS® scoring service, descriptive statistics, and t-tests. We received completed surveys from 223 parents of individuals with DS; previously published limitations of the instrument in this population were shown again. T-scores differed from the available comparative standardized scores to these measures from PROMIS® reference population on Fatigue (p < 0.001) and Global Health (p < 0.001), but not on Pain Interference (p = 0.41).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37639895,
title = {Cortisol in deciduous tooth tissues: A potential metric for assessing stress exposure in archaeological and living populations},
author = {Leslie Quade and Miroslav Králík and Petra Bencúrová and Erin C Dunn},
doi = {10.1016/j.ijpp.2023.08.001},
issn = {1879-9825},
year  = {2023},
date = {2023-08-01},
journal = {Int J Paleopathol},
volume = {43},
pages = {1--6},
abstract = {OBJECTIVE: Cortisol is a glucocorticoid hormone produced by the hypothalamic-pituitary-adrenal axis that is regularly assessed in modern human and non-human populations in saliva, blood, and hair as a measure of stress exposure and stress reactivity. While recent research has detected cortisol concentrations in modern and archaeological permanent dental tissues, the present study assessed human primary (deciduous) teeth for cortisol concentrations.nnMATERIALS AND METHODS: Fifty-one dentine and enamel samples from nine modern and 10 archaeological deciduous teeth were analyzed for cortisol concentrations via enzyme-linked immunosorbent assay (ELISA).nnRESULTS: Detectable concentrations of cortisol were identified in 15 (of 32) dentine and 8 (of 19) enamel samples coming from modern and archaeological deciduous teeth.nnCONCLUSIONS: This study is the first known analysis of cortisol from deciduous dental tissues, demonstrating the potential to identify measurable concentrations.nnSIGNIFICANCE: The ability to analyze deciduous teeth is integral to developing dental cortisol methods with multiple potential future applications, including research on the biological embedding of stress in the skeleton. This study marks a key step in a larger research program to study stress in primary dentition from living and archaeological populations.nnLIMITATIONS: Multiple samples generated cortisol values that were not detectable with ELISA. Minimum quantities of tissue may be required to generate detectable levels of cortisol.nnSUGGESTIONS FOR FURTHER RESEARCH: Future research should include larger sample sizes and consideration of intrinsic biological and extrinsic preservation factors on dental cortisol. Further method validation and alternative methods for assessing dental cortisol are needed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37264986,
title = {Views on the impact of the COVID-19 pandemic on health in people with Down syndrome from diverse backgrounds},
author = {Stephanie L Santoro and Sandra Baker and Jasmine M Blake and Maria J Cabrera and Kelli Caughman and Jeanhee Chung and Sarah Cullen and Maureen Gallagher and Kelsey Haugen and Roxanne Hoke-Chandler and Kavita Krell and Julius Maina and Diana McLuckie and Vanessa L Merker and Carie Michael and Kate O'Neill and Angeles Peña and Albert Pless and Dina Royal and Michelle Slape and Noemi Alice Spinazzi and Amy Torres and Carlos G Torres and Brian G Skotko},
doi = {10.1002/ajmg.a.63233},
issn = {1552-4833},
year  = {2023},
date = {2023-08-01},
journal = {Am J Med Genet A},
volume = {191},
number = {8},
pages = {2045--2056},
abstract = {Down syndrome (DS) has a unique medical and psychological profile. To date, few studies have asked individuals with DS about their views of health, and fewer have explored the impact of COVID-19 on the health of individuals with DS and their families. We used a mixed methods approach including two studies on the health of individuals with DS and their parents conducted during the COVID-19 pandemic: (1) eight virtual focus groups, comprised of 20 parents and 8 individuals with DS to obtain participants' views of health, and (2) a 20-item questionnaire on health care experience of patients with DS who are African American or come from primarily Spanish-speaking homes. Focus group transcripts were coded using a hybrid inductive/deductive framework and thematically analyzed using the Framework Method. This questionnaire included questions regarding the impact of COVID-19 on caregivers and their loved ones with DS; responses to these questions were summarized using descriptive statistics. Individuals with DS discussed the impact of the COVID-19 pandemic on their physical and social health including masking, online learning, and online communication with friends and family. Parents of individuals with DS discussed how the COVID-19 pandemic negatively impacted their child's physical, social, and mental health, as a result of virtual schooling and decreased socialization. There were unexpected positives of the pandemic such as improved hygiene and eased scheduling with telehealth visits. Caregivers noted COVID-19 impacted their own anxiety, employment, and other domains that have potential ripple effects on the health of their children. The COVID-19 pandemic had a pervasive impact on the mental health and wellness of caregivers as well as the physical, social, and mental health of individuals with DS.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37609236,
title = {Sensitive periods for exposure to indoor air pollutants and psychosocial factors in association with symptoms of psychopathology at school-age in a South African birth cohort},
author = {Grace M Christensen and Michele Marcus and Aneesa Vanker and Stephanie M Eick and Susan Malcolm-Smith and Andrew D A C Smith and Erin C Dunn and Shakira F Suglia and Howard H Chang and Heather J Zar and Dan J Stein and Anke Hüls},
doi = {10.1101/2023.08.08.23293825},
year  = {2023},
date = {2023-08-01},
journal = {medRxiv},
abstract = {BACKGROUND: Gestation and the first few months of life are important periods for brain development. During these periods, exposure to environmental toxicants and psychosocial stressors are particularly harmful and may impact brain development. Specifically, exposure to indoor air pollutants (IAP) and psychosocial factors (PF) during these sensitive periods has been shown to predict childhood psychopathology.nnOBJECTIVES: This study aims to investigate sensitive periods for the individual and joint effects of IAP and PF on childhood psychopathology at 6.5 years.nnMETHODS: We analyzed data from the Drakenstein Child Health Study (N=599), a South African birth cohort. Exposure to IAP and PF was measured during the second trimester of pregnancy and 4 months postpartum. The outcome of childhood psychopathology was assessed at 6.5 years old using the Childhood Behavior Checklist (CBCL). We investigated individual effects of either pre-or postnatal exposure to IAP and PF on CBCL scores using adjusted linear regression models, and joint effects of these exposures using quantile g-computation and self-organizing maps (SOM). To identify possible sensitive periods, we used a structured life course modeling approach (SLCMA) as well as exposure mixture methods (quantile g-computation and SOM).nnRESULTS: Prenatal exposure to IAP or PFs, as well as the total prenatal mixture assessed using quantile g-computation, were associated with increased psychopathology. SLCMA and SOM models also indicated that the prenatal period is a sensitive period for IAP exposure on childhood psychopathology. Depression and alcohol were associated in both the pre-and postnatal period, while CO was associated with the postnatal period.nnDISCUSSION: Pregnancy may be a sensitive period for the effect of indoor air pollution on childhood psychopathology. Exposure to maternal depression and alcohol in both periods was also associated with psychopathology. Determining sensitive periods of exposure is vital to ensure effective interventions to reduce childhood psychopathology.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37573007,
title = {Loss of Function in the Neurodevelopmental Disease and Schizophrenia-Associated Gene CYFIP1 in Human Microglia-Like Cells Supports a Functional Role in Synaptic Engulfment},
author = {Steven D Sheridan and Joy E Horng and Hana Yeh and Liam McCrea and Jennifer Wang and Ting Fu and Roy H Perlis},
doi = {10.1016/j.biopsych.2023.07.022},
issn = {1873-2402},
year  = {2023},
date = {2023-08-01},
journal = {Biol Psychiatry},
abstract = {BACKGROUND: The CYFIP1 gene, located in the neurodevelopmental risk locus 15q11.2, is highly expressed in microglia, but its role in human microglial function as it relates to neurodevelopment is not well understood.nnMETHODS: We generated multiple CRISPR knockouts of CYFIP1 in patient-derived models of microglia to characterize function and phenotype. Using microglia-like cells reprogrammed from peripheral blood mononuclear cells, we quantified phagocytosis of synaptosomes (isolated and purified synaptic vesicles) from human iPSC-derived neuronal cultures as an in vitro model of synaptic pruning. We repeated these analyses in human iPSC-derived microglia-like cells (iMGLCs) derived from three isogenic wild-type/knockout line pairs derived from two donors and further characterized microglial development and function through morphology and motility.nnRESULTS: CYFIP1 knockout using orthogonal CRISPR constructs in multiple patient-derived cell lines was associated with statistically significant decrease in synaptic vesicle phagocytosis in microglia-like cell models derived from both PBMCs and iPSCs. Morphology was also shifted toward a more ramified profile, and motility was significantly reduced. However, iPSC-CYFIP1 knockout lines retained the ability to differentiate to functional microglia.nnCONCLUSION: The changes in microglial phenotype and function due to the loss of function of CYFIP1 observed in this study implicate a potential impact on processes such as synaptic pruning that may contribute to CYFIP1-related neurodevelopmental disorders. Investigating risk genes in a range of CNS cell types, not solely neurons, may be required to fully understand the way in which common and rare variants intersect to yield neuropsychiatric disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36894722,
title = {Sniper2L is a high-fidelity Cas9 variant with high activity},
author = {Young-Hoon Kim and Nahye Kim and Ikenna Okafor and Sungchul Choi and Seonwoo Min and Joonsun Lee and Seung-Min Bae and Keunwoo Choi and Janice Choi and Vinayak Harihar and Youngho Kim and Jin-Soo Kim and Benjamin P Kleinstiver and Jungjoon K Lee and Taekjip Ha and Hyongbum Henry Kim},
doi = {10.1038/s41589-023-01279-5},
issn = {1552-4469},
year  = {2023},
date = {2023-08-01},
journal = {Nat Chem Biol},
volume = {19},
number = {8},
pages = {972--980},
abstract = {Although several high-fidelity SpCas9 variants have been reported, it has been observed that this increased specificity is associated with reduced on-target activity, limiting the applications of the high-fidelity variants when efficient genome editing is required. Here, we developed an improved version of Sniper-Cas9, Sniper2L, which represents an exception to this trade-off trend as it showed higher specificity with retained high activity. We evaluated Sniper2L activities at a large number of target sequences and developed DeepSniper, a deep learning model that can predict the activity of Sniper2L. We also confirmed that Sniper2L can induce highly efficient and specific editing at a large number of target sequences when it is delivered as a ribonucleoprotein complex. Mechanically, the high specificity of Sniper2L originates from its superior ability to avoid unwinding a target DNA containing even a single mismatch. We envision that Sniper2L will be useful when efficient and specific genome editing is required.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37314780,
title = {Transcriptome-Wide Structural Equation Modeling of 13 Major Psychiatric Disorders for Cross-Disorder Risk and Drug Repurposing},
author = {Andrew D Grotzinger and Kritika Singh and Tyne W Miller-Fleming and Max Lam and Travis T Mallard and Yu Chen and Zhaowen Liu and Tian Ge and Jordan W Smoller},
doi = {10.1001/jamapsychiatry.2023.1808},
issn = {2168-6238},
year  = {2023},
date = {2023-08-01},
journal = {JAMA Psychiatry},
volume = {80},
number = {8},
pages = {811--821},
abstract = {IMPORTANCE: Psychiatric disorders display high levels of comorbidity and genetic overlap, necessitating multivariate approaches for parsing convergent and divergent psychiatric risk pathways. Identifying gene expression patterns underlying cross-disorder risk also stands to propel drug discovery and repurposing in the face of rising levels of polypharmacy.nnOBJECTIVE: To identify gene expression patterns underlying genetic convergence and divergence across psychiatric disorders along with existing pharmacological interventions that target these genes.nnDESIGN, SETTING, AND PARTICIPANTS: This genomic study applied a multivariate transcriptomic method, transcriptome-wide structural equation modeling (T-SEM), to investigate gene expression patterns associated with 5 genomic factors indexing shared risk across 13 major psychiatric disorders. Follow-up tests, including overlap with gene sets for other outcomes and phenome-wide association studies, were conducted to better characterize T-SEM results. The Broad Institute Connectivity Map Drug Repurposing Database and Drug-Gene Interaction Database public databases of drug-gene pairs were used to identify drugs that could be repurposed to target genes found to be associated with cross-disorder risk. Data were collected from database inception up to February 20, 2023.nnMAIN OUTCOMES AND MEASURES: Gene expression patterns associated with genomic factors or disorder-specific risk and existing drugs that target these genes.nnRESULTS: In total, T-SEM identified 466 genes whose expression was significantly associated (z ≥ 5.02) with genomic factors and 36 genes with disorder-specific effects. Most associated genes were found for a thought disorders factor, defined by bipolar disorder and schizophrenia. Several existing pharmacological interventions were identified that could be repurposed to target genes whose expression was associated with the thought disorders factor or a transdiagnostic p factor defined by all 13 disorders.nnCONCLUSIONS AND RELEVANCE: The findings from this study shed light on patterns of gene expression associated with genetic overlap and uniqueness across psychiatric disorders. Future versions of the multivariate drug repurposing framework outlined here have the potential to identify novel pharmacological interventions for increasingly common, comorbid psychiatric presentations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37489536,
title = {Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women},
author = {Art Schuermans and Tetsushi Nakao and Md Mesbah Uddin and Whitney Hornsby and Shriie Ganesh and Aladdin H Shadyab and Simin Liu and Bernhard Haring and Chrisandra L Shufelt and Margaret A Taub and Rasika A Mathias and Charles Kooperberg and Alexander P Reiner and Alexander G Bick and JoAnn E Manson and Pradeep Natarajan and Michael C Honigberg},
doi = {10.1161/CIRCRESAHA.123.322984},
issn = {1524-4571},
year  = {2023},
date = {2023-08-01},
journal = {Circ Res},
volume = {133},
number = {5},
pages = {376--386},
abstract = {BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease.nnMETHODS: Participants from the UK Biobank and Women's Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease.nnRESULTS: This study included 130 254 postmenopausal women (UK Biobank: n=122 224; Women's Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; =7.2×10). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; <2.2×10) and was independent of hormone therapy use. Mendelian randomization supported a causal association of shorter genetically predicted LTL with earlier age at natural menopause. LTL and age at menopause were independently associated with incident coronary artery disease, and mediation analyses indicated small but significant mediation effects of LTL in the association of menopausal age with coronary artery disease.nnCONCLUSIONS: Earlier age at menopause is associated with shorter LTL, especially among women with natural menopause. Accelerated telomere shortening may contribute to the heightened cardiovascular risk associated with premature menopause.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37400429,
title = {Publisher Correction: Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality},
author = {Asmundur Oddsson and Patrick Sulem and Gardar Sveinbjornsson and Gudny A Arnadottir and Valgerdur Steinthorsdottir and Gisli H Halldorsson and Bjarni A Atlason and Gudjon R Oskarsson and Hannes Helgason and Henriette Svarre Nielsen and David Westergaard and Juha M Karjalainen and Hildigunnur Katrinardottir and Run Fridriksdottir and Brynjar O Jensson and Vinicius Tragante and Egil Ferkingstad and Hakon Jonsson and Sigurjon A Gudjonsson and Doruk Beyter and Kristjan H S Moore and Helga B Thordardottir and Snaedis Kristmundsdottir and Olafur A Stefansson and Solbritt Rantapää-Dahlqvist and Ida Elken Sonderby and Maria Didriksen and Pernilla Stridh and Jan Haavik and Laufey Tryggvadottir and Oleksandr Frei and G Bragi Walters and Ingrid Kockum and Henrik Hjalgrim and Thorunn A Olafsdottir and Geir Selbaek and Mette Nyegaard and Christian Erikstrup and Thorsten Brodersen and Saedis Saevarsdottir and Tomas Olsson and Kaspar Rene Nielsen and Asgeir Haraldsson and Mie Topholm Bruun and Thomas Folkmann Hansen and  and Thora Steingrimsdottir and Rikke Louise Jacobsen and Rolv T Lie and Srdjan Djurovic and Lars Alfredsson and Aitzkoa Lopez de Lapuente Portilla and Soren Brunak and Pall Melsted and Bjarni V Halldorsson and Jona Saemundsdottir and Olafur Th Magnusson and Leonid Padyukov and Karina Banasik and Thorunn Rafnar and Johan Askling and Lars Klareskog and Ole Birger Pedersen and Gisli Masson and Alexandra Havdahl and Bjorn Nilsson and Ole A Andreassen and Mark Daly and Sisse Rye Ostrowski and Ingileif Jonsdottir and Hreinn Stefansson and Hilma Holm and Agnar Helgason and Unnur Thorsteinsdottir and Kari Stefansson and Daniel F Gudbjartsson},
doi = {10.1038/s41467-023-39492-4},
issn = {2041-1723},
year  = {2023},
date = {2023-07-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {3923},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37148359,
title = {The power of TOPMed imputation for the discovery of Latino-enriched rare variants associated with type 2 diabetes},
author = {Alicia Huerta-Chagoya and Philip Schroeder and Ravi Mandla and Aaron J Deutsch and Wanying Zhu and Lauren Petty and Xiaoyan Yi and Joanne B Cole and Miriam S Udler and Peter Dornbos and Bianca Porneala and Daniel DiCorpo and Ching-Ti Liu and Josephine H Li and Lukasz Szczerbiński and Varinderpal Kaur and Joohyun Kim and Yingchang Lu and Alicia Martin and Decio L Eizirik and Piero Marchetti and Lorella Marselli and Ling Chen and Shylaja Srinivasan and Jennifer Todd and Jason Flannick and Rose Gubitosi-Klug and Lynne Levitsky and Rachana Shah and Megan Kelsey and Brian Burke and Dana M Dabelea and Jasmin Divers and Santica Marcovina and Lauren Stalbow and Ruth J F Loos and Burcu F Darst and Charles Kooperberg and Laura M Raffield and Christopher Haiman and Quan Sun and Joseph B McCormick and Susan P Fisher-Hoch and Maria L Ordoñez and James Meigs and Leslie J Baier and Clicerio González-Villalpando and Maria Elena González-Villalpando and Lorena Orozco and Lourdes García-García and Andrés Moreno-Estrada and  and Carlos A Aguilar-Salinas and Teresa Tusié and Josée Dupuis and Maggie C Y Ng and Alisa Manning and Heather M Highland and Miriam Cnop and Robert Hanson and Jennifer Below and Jose C Florez and Aaron Leong and Josep M Mercader},
doi = {10.1007/s00125-023-05912-9},
issn = {1432-0428},
year  = {2023},
date = {2023-07-01},
journal = {Diabetologia},
volume = {66},
number = {7},
pages = {1273--1288},
abstract = {AIMS/HYPOTHESIS: The Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population.nnMETHODS: We evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort.nnRESULTS: Compared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p=3.4 × 10). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance.nnCONCLUSIONS/INTERPRETATION: Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores.nnDATA AVAILABILITY: Full summary statistics are available through the Common Metabolic Diseases Knowledge Portal ( https://t2d.hugeamp.org/downloads.html ) and through the GWAS catalog ( https://www.ebi.ac.uk/gwas/ , accession ID: GCST90255648). Polygenic score (PS) weights for each ancestry are available via the PGS catalog ( https://www.pgscatalog.org , publication ID: PGP000445, scores IDs: PGS003443, PGS003444 and PGS003445).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37212139,
title = {Risk of Midlife Stroke After Adverse Pregnancy Outcomes: The FinnGen Study},
author = {Eliza C Miller and Anni Kauko and Sarah E Tom and Hannele Laivuori and Teemu Niiranen and Natalie A Bello and },
doi = {10.1161/STROKEAHA.123.043052},
issn = {1524-4628},
year  = {2023},
date = {2023-07-01},
journal = {Stroke},
volume = {54},
number = {7},
pages = {1798--1805},
abstract = {BACKGROUND: Adverse pregnancy outcomes (APO) contribute to higher risk of maternal cerebrovascular disease, but longitudinal data that include APO and stroke timing are lacking. We hypothesized that APO are associated with younger age at first stroke, with a stronger relationship in those with >1 pregnancy with APO.nnMETHODS: We analyzed longitudinal Finnish nationwide health registry data from the FinnGen Study. We included women who gave birth after 1969 when the hospital discharge registry was established. We defined APO as a pregnancy affected by gestational hypertension, preeclampsia, eclampsia, preterm birth, small for gestational age infant, or placental abruption. We defined stroke as first hospital admission for ischemic stroke or nontraumatic intracerebral or subarachnoid hemorrhage, excluding stroke during pregnancy or within 1 year postpartum. We used Kaplan-Meier survival curves and multivariable-adjusted Cox and generalized linear models to assess the relationship between APO and future stroke.nnRESULTS: We included 144 306 women with a total of 316 789 births in the analysis sample, of whom 17.9% had at least 1 pregnancy with an APO and 2.9% experienced an APO in ≥2 pregnancies. Women with APO had more comorbidities including obesity, hypertension, heart disease, and migraine. Median age at first stroke was 58.3 years in those with no APO, 54.8 years in those with 1 APO, and 51.6 years in those with recurrent APO. In models adjusted for sociodemographic characteristics and stroke risk factors, risk of stroke was greater in women with 1 APO (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.4]) and recurrent APO (adjusted hazard ratio, 1.4 [95% CI, 1.2-1.7]) compared with those with no APO. Women with recurrent APO had more than twice the stroke risk before age 45 (adjusted odds ratio, 2.1 [95% CI, 1.5-3.1]) compared with those without APO.nnCONCLUSIONS: Women who experience APO have earlier onset of cerebrovascular disease, with the earliest onset in those with more than 1 affected pregnancy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37322115,
title = {Clonal hematopoiesis is associated with protection from Alzheimer's disease},
author = {Hind Bouzid and Julia A Belk and Max Jan and Yanyan Qi and Chloé Sarnowski and Sara Wirth and Lisa Ma and Matthew R Chrostek and Herra Ahmad and Daniel Nachun and Winnie Yao and  and Alexa Beiser and Alexander G Bick and Joshua C Bis and Myriam Fornage and William T Longstreth and Oscar L Lopez and Pradeep Natarajan and Bruce M Psaty and Claudia L Satizabal and Joshua Weinstock and Eric B Larson and Paul K Crane and C Dirk Keene and Sudha Seshadri and Ansuman T Satpathy and Thomas J Montine and Siddhartha Jaiswal},
doi = {10.1038/s41591-023-02397-2},
issn = {1546-170X},
year  = {2023},
date = {2023-07-01},
journal = {Nat Med},
volume = {29},
number = {7},
pages = {1662--1670},
abstract = {Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36593413,
title = {Precise cut-and-paste DNA insertion using engineered type V-K CRISPR-associated transposases},
author = {Connor J Tou and Benno Orr and Benjamin P Kleinstiver},
doi = {10.1038/s41587-022-01574-x},
issn = {1546-1696},
year  = {2023},
date = {2023-07-01},
journal = {Nat Biotechnol},
volume = {41},
number = {7},
pages = {968--979},
abstract = {CRISPR-associated transposases (CASTs) enable recombination-independent, multi-kilobase DNA insertions at RNA-programmed genomic locations. However, the utility of type V-K CASTs is hindered by high off-target integration and a transposition mechanism that results in a mixture of desired simple cargo insertions and undesired plasmid cointegrate products. Here we overcome both limitations by engineering new CASTs with improved integration product purity and genome-wide specificity. To do so, we engineered a nicking homing endonuclease fusion to TnsB (named HELIX) to restore the 5' nicking capability needed for cargo excision on the DNA donor. HELIX enables cut-and-paste DNA insertion with up to 99.4% simple insertion product purity, while retaining robust integration efficiencies on genomic targets. HELIX has substantially higher on-target specificity than canonical CASTs, and we identify several novel factors that further regulate targeted and genome-wide integration. Finally, we extend HELIX to other type V-K orthologs and demonstrate the feasibility of HELIX-mediated integration in human cell contexts.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37198333,
title = {De novo MCM6 variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues},
author = {Daphne J Smits and Rachel Schot and Cristiana A Popescu and Kerith-Rae Dias and Lesley Ades and Lauren C Briere and David A Sweetser and Itaru Kushima and Branko Aleksic and Suliman Khan and Vasiliki Karageorgou and Natalia Ordonez and Frank J G T Sleutels and Daniëlle C M van der Kaay and Christine Van Mol and Hilde Van Esch and Aida M Bertoli-Avella and Tony Roscioli and Grazia M S Mancini},
doi = {10.1007/s00439-023-02569-7},
issn = {1432-1203},
year  = {2023},
date = {2023-07-01},
journal = {Hum Genet},
volume = {142},
number = {7},
pages = {949--964},
abstract = {The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier-Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37160117,
title = {Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis},
author = {Máté G Kiss and John E Mindur and Abi G Yates and Donghoon Lee and John F Fullard and Atsushi Anzai and Wolfram C Poller and Kathleen A Christie and Yoshiko Iwamoto and Vladimir Roudko and Jeffrey Downey and Christopher T Chan and Pacific Huynh and Henrike Janssen and Achilles Ntranos and Jan D Hoffmann and Walter Jacob and Sukanya Goswami and Sumnima Singh and David Leppert and Jens Kuhle and Seunghee Kim-Schulze and Matthias Nahrendorf and Benjamin P Kleinstiver and Fay Probert and Panos Roussos and Filip K Swirski and Cameron S McAlpine},
doi = {10.1016/j.immuni.2023.04.013},
issn = {1097-4180},
year  = {2023},
date = {2023-07-01},
journal = {Immunity},
volume = {56},
number = {7},
pages = {1502--1514.e8},
abstract = {Glial cells and central nervous system (CNS)-infiltrating leukocytes contribute to multiple sclerosis (MS). However, the networks that govern crosstalk among these ontologically distinct populations remain unclear. Here, we show that, in mice and humans, CNS-resident astrocytes and infiltrating CD44CD4 T cells generated interleukin-3 (IL-3), while microglia and recruited myeloid cells expressed interleukin-3 receptor-ɑ (IL-3Rɑ). Astrocytic and T cell IL-3 elicited an immune migratory and chemotactic program by IL-3Rɑ myeloid cells that enhanced CNS immune cell infiltration, exacerbating MS and its preclinical model. Multiregional snRNA-seq of human CNS tissue revealed the appearance of IL3RA-expressing myeloid cells with chemotactic programming in MS plaques. IL3RA expression by plaque myeloid cells and IL-3 amount in the cerebrospinal fluid predicted myeloid and T cell abundance in the CNS and correlated with MS severity. Our findings establish IL-3:IL-3RA as a glial-peripheral immune network that prompts immune cell recruitment to the CNS and worsens MS.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37301713,
title = {The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections},
author = {Samuel E Jones and Fahrisa I Maisha and Satu J Strausz and Vilma Lammi and Brian E Cade and Anniina Tervi and Viola Helaakoski and Martin E Broberg and  and Jacqueline M Lane and Susan Redline and Richa Saxena and Hanna M Ollila},
doi = {10.1016/j.ebiom.2023.104630},
issn = {2352-3964},
year  = {2023},
date = {2023-07-01},
journal = {EBioMedicine},
volume = {93},
pages = {104630},
abstract = {BACKGROUND: Poor sleep is associated with an increased risk of infections and all-cause mortality but the causal direction between poor sleep and respiratory infections has remained unclear. We examined if poor sleep contributes as a causal risk factor to respiratory infections.nnMETHODS: We used data on insomnia, influenza and upper respiratory infections (URIs) from primary care and hospital records in the UK Biobank (N ≈ 231,000) and FinnGen (N ≈ 392,000). We computed logistic regression to assess association between poor sleep and infections, disease free survival hazard ratios, and performed Mendelian randomization analyses to assess causality.nnFINDINGS: Utilizing 23 years of registry data and follow-up, we discovered that insomnia diagnosis associated with increased risk for infections (FinnGen influenza Cox's proportional hazard (CPH) HR = 4.34 [3.90, 4.83], P = 4.16 × 10, UK Biobank influenza CPH HR = 1.54 [1.37, 1.73], P = 2.49 × 10). Mendelian randomization indicated that insomnia causally predisposed to influenza (inverse-variance weighted (IVW) OR = 1.65, P = 5.86 × 10), URI (IVW OR = 1.94, P = 8.14 × 10), COVID-19 infection (IVW OR = 1.08, P = 0.037) and risk of hospitalization from COVID-19 (IVW OR = 1.47, P = 4.96 × 10).nnINTERPRETATION: Our findings indicate that chronic poor sleep is a causal risk factor for contracting respiratory infections, and in addition contributes to the severity of respiratory infections. These findings highlight the role of sleep in maintaining sufficient immune response against pathogens.nnFUNDING: Instrumentarium Science Foundation, Academy of Finland, Signe and Ane Gyllenberg Foundation, National Institutes of Health.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37464041,
title = {Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses},
author = {Thomas D Als and Mitja I Kurki and Jakob Grove and Georgios Voloudakis and Karen Therrien and Elisa Tasanko and Trine Tollerup Nielsen and Joonas Naamanka and Kumar Veerapen and Daniel F Levey and Jaroslav Bendl and Jonas Bybjerg-Grauholm and Biao Zeng and Ditte Demontis and Anders Rosengren and Georgios Athanasiadis and Marie Bækved-Hansen and Per Qvist and G Bragi Walters and Thorgeir Thorgeirsson and Hreinn Stefánsson and Katherine L Musliner and Veera M Rajagopal and Leila Farajzadeh and Janne Thirstrup and Bjarni J Vilhjálmsson and John J McGrath and Manuel Mattheisen and Sandra Meier and Esben Agerbo and Kári Stefánsson and Merete Nordentoft and Thomas Werge and David M Hougaard and Preben B Mortensen and Murray B Stein and Joel Gelernter and Iiris Hovatta and Panos Roussos and Mark J Daly and Ole Mors and Aarno Palotie and Anders D Børglum},
doi = {10.1038/s41591-023-02352-1},
issn = {1546-170X},
year  = {2023},
date = {2023-07-01},
journal = {Nat Med},
volume = {29},
number = {7},
pages = {1832--1844},
abstract = {Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37233759,
title = {Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH},
author = {Josephine H Li and Laura N Brenner and Varinderpal Kaur and Katherine Figueroa and Philip Schroeder and Alicia Huerta-Chagoya and  and  and Miriam S Udler and Aaron Leong and Josep M Mercader and Jose C Florez},
doi = {10.1007/s00125-023-05922-7},
issn = {1432-0428},
year  = {2023},
date = {2023-07-01},
journal = {Diabetologia},
volume = {66},
number = {7},
pages = {1260--1272},
abstract = {AIMS/HYPOTHESIS: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes.nnMETHODS: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals.nnRESULTS: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAF]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAF=0.0536), was associated with a reduced response to metformin (p=2.4×10), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA of 0.08% and non-carriers had an HbA increase of 0.01% after 1 year of treatment (p=3.3×10). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6×10), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology.nnCONCLUSIONS/INTERPRETATION: We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation.nnDATA AVAILABILITY: The complete summary statistics from this study are available at the Common Metabolic Diseases Knowledge Portal ( https://hugeamp.org ) and the GWAS Catalog ( www.ebi.ac.uk/gwas/ , accession IDs: GCST90269867 to GCST90269899).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37438363,
title = {A model for organization and regulation of nuclear condensates by gene activity},
author = {Halima H Schede and Pradeep Natarajan and Arup K Chakraborty and Krishna Shrinivas},
doi = {10.1038/s41467-023-39878-4},
issn = {2041-1723},
year  = {2023},
date = {2023-07-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {4152},
abstract = {Condensation by phase separation has recently emerged as a mechanism underlying many nuclear compartments essential for cellular functions. Nuclear condensates enrich nucleic acids and proteins, localize to specific genomic regions, and often promote gene expression. How diverse properties of nuclear condensates are shaped by gene organization and activity is poorly understood. Here, we develop a physics-based model to interrogate how spatially-varying transcription activity impacts condensate properties and dynamics. Our model predicts that spatial clustering of active genes can enable precise localization and de novo nucleation of condensates. Strong clustering and high activity results in aspherical condensate morphologies. Condensates can flow towards distant gene clusters and competition between multiple clusters lead to stretched morphologies and activity-dependent repositioning. Overall, our model predicts and recapitulates morphological and dynamical features of diverse nuclear condensates and offers a unified mechanistic framework to study the interplay between non-equilibrium processes, spatially-varying transcription, and multicomponent condensates in cell biology.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37461573,
title = {Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank},
author = {Frederik H Lassen and Samvida S Venkatesh and Nikolas Baya and Wei Zhou and Alex Bloemendal and Benjamin M Neale and Benedikt M Kessler and Nicola Whiffin and Cecilia M Lindgren and Duncan S Palmer},
doi = {10.1101/2023.06.29.23291992},
year  = {2023},
date = {2023-07-01},
journal = {medRxiv},
abstract = {Exome-sequencing association studies have successfully linked rare protein-coding variation to risk of thousands of diseases. However, the relationship between rare deleterious compound heterozygous (CH) variation and their phenotypic impact has not been fully investigated. Here, we leverage advances in statistical phasing to accurately phase rare variants (MAF ∼ 0.001%) in exome sequencing data from 175,587 UK Biobank (UKBB) participants, which we then systematically annotate to identify putatively deleterious CH coding variation. We show that 6.5% of individuals carry such damaging variants in the CH state, with 90% of variants occurring at MAF < 0.34%. Using a logistic mixed model framework, systematically accounting for relatedness, polygenic risk, nearby common variants, and rare variant burden, we investigate recessive effects in common complex diseases. We find six exome-wide significant (𝑃 < 1.68 × 10  ) and 17 nominally significant (𝑃 < 5.25 × 10  ) gene-trait associations. Among these, only four would have been identified without accounting for CH variation in the gene. We further incorporate age-at-diagnosis information from primary care electronic health records, to show that genetic phase influences lifetime risk of disease across 20 gene-trait combinations (FDR < 5%). Using a permutation approach, we find evidence for genetic phase contributing to disease susceptibility for a collection of gene-trait pairs, including  -asthma (𝑃 = 0.00205) and  -visual impairment (𝑃 = 0.0084). Taken together, we demonstrate the utility of phasing large-scale genetic sequencing cohorts for robust identification of the phenome-wide consequences of compound heterozygosity.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37502976,
title = {Allelic strengths of encephalopathy-associated  variants correlate between  and  assays},
author = {Xueyang Pan and Albert N Alvarez and Mengqi Ma and Shenzhao Lu and Michael W Crawford and Lauren C Briere and Oguz Kanca and Shinya Yamamoto and David A Sweetser and Jenny L Wilson and Ruth J Napier and Jonathan N Pruneda and Hugo J Bellen},
doi = {10.1101/2023.07.17.23292782},
year  = {2023},
date = {2023-07-01},
journal = {medRxiv},
abstract = {Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and ER stress. Variants in the  gene are associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global developmental delay, intellectual disability, and seizures. DEE44 is caused by at least twelve different missense variants described as loss of function (LoF), but the relationships between genotypes and molecular or clinical phenotypes remains to be established. We developed a humanized  fly model and biochemical activity assays in order to describe  and  genotype-phenotype relationships across the  allelic series.  , we observed a broad spectrum of phenotypes in viability, developmental timing, lifespan, locomotor activity, and bang sensitivity. A range of functional effects was also observed  across comprehensive biochemical assays for protein stability, ATP binding, UFM1 activation, and UFM1 transthiolation. Importantly, there is a strong correlation between  and  phenotypes, establishing a classification of LoF variants into mild, intermediate, and severe allelic strengths. By systemically evaluating  variants across  and  platforms, this study provides a foundation for more basic and translational UBA5 research, as well as a basis for evaluating current and future individuals afflicted with this rare disease.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37352859,
title = {Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup},
author = {Logan C Walker and Miguel de la Hoya and George A R Wiggins and Amanda Lindy and Lisa M Vincent and Michael T Parsons and Daffodil M Canson and Dana Bis-Brewer and Ashley Cass and Alexander Tchourbanov and Heather Zimmermann and Alicia B Byrne and Tina Pesaran and Rachid Karam and Steven M Harrison and Amanda B Spurdle and },
doi = {10.1016/j.ajhg.2023.06.002},
issn = {1537-6605},
year  = {2023},
date = {2023-07-01},
journal = {Am J Hum Genet},
volume = {110},
number = {7},
pages = {1046--1067},
abstract = {The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) framework for classifying variants uses six evidence categories related to the splicing potential of variants: PVS1, PS3, PP3, BS3, BP4, and BP7. However, the lack of guidance on how to apply such codes has contributed to variation in the specifications developed by different Clinical Genome Resource (ClinGen) Variant Curation Expert Panels. The ClinGen Sequence Variant Interpretation Splicing Subgroup was established to refine recommendations for applying ACMG/AMP codes relating to splicing data and computational predictions. We utilized empirically derived splicing evidence to (1) determine the evidence weighting of splicing-related data and appropriate criteria code selection for general use, (2) outline a process for integrating splicing-related considerations when developing a gene-specific PVS1 decision tree, and (3) exemplify methodology to calibrate splice prediction tools. We propose repurposing the PVS1_Strength code to capture splicing assay data that provide experimental evidence for variants resulting in RNA transcript(s) with loss of function. Conversely, BP7 may be used to capture RNA results demonstrating no splicing impact for intronic and synonymous variants. We propose that the PS3/BS3 codes are applied only for well-established assays that measure functional impact not directly captured by RNA-splicing assays. We recommend the application of PS1 based on similarity of predicted RNA-splicing effects for a variant under assessment in comparison with a known pathogenic variant. The recommendations and approaches for consideration and evaluation of RNA-assay evidence described aim to help standardize variant pathogenicity classification processes when interpreting splicing-based evidence.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37507766,
title = {Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia},
author = {Annie Kathuria and Kara Lopez-Lengowski and Bradley Watmuff and Rakesh Karmacharya},
doi = {10.1186/s13073-023-01203-5},
issn = {1756-994X},
year  = {2023},
date = {2023-07-01},
journal = {Genome Med},
volume = {15},
number = {1},
pages = {58},
abstract = {BACKGROUND: Postmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown. Recent genome-wide association studies and exome sequencing investigations implicate synaptic genes and processes in the disease biology of schizophrenia.nnMETHODS: We generated human cortical pyramidal neurons by differentiating iPSCs of seven schizophrenia patients and seven healthy subjects, quantified dendritic spines and synapses in different cortical neuron subtypes, and carried out transcriptomic studies to identify differentially regulated genes and aberrant cellular processes in schizophrenia.nnRESULTS: Cortical neurons expressing layer III marker CUX1, but not those expressing layer V marker CTIP2, showed significant reduction in dendritic spine density in schizophrenia, mirroring findings in postmortem studies. Transcriptomic experiments in iPSC-derived cortical neurons showed that differentially expressed genes in schizophrenia were enriched for genes implicated in schizophrenia in genome-wide association and exome sequencing studies. Moreover, most of the differentially expressed genes implicated in schizophrenia genetic studies had lower expression levels in schizophrenia cortical neurons. Network analysis of differentially expressed genes led to identification of NRXN3 as a hub gene, and follow-up experiments showed specific reduction of the NRXN3 204 isoform in schizophrenia neurons. Furthermore, overexpression of the NRXN3 204 isoform in schizophrenia neurons rescued the spine and synapse deficits in the cortical neurons while knockdown of NRXN3 204 in healthy neurons phenocopied spine and synapse deficits seen in schizophrenia cortical neurons. The antipsychotic clozapine increased expression of the NRXN3 204 isoform in schizophrenia cortical neurons and rescued the spine and synapse density deficits.nnCONCLUSIONS: Taken together, our findings in iPSC-derived cortical neurons recapitulate cell type-specific findings in postmortem studies in schizophrenia and have led to the identification of a specific isoform of NRXN3 that modulates synaptic deficits in schizophrenia neurons.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37546893,
title = {Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus},
author = {Soo Heon Kwak and Ryan B Hernandez-Cancela and Daniel A DiCorpo and David E Condon and Jordi Merino and Peitao Wu and Jennifer A Brody and Jie Yao and Xiuqing Guo and Fariba Ahmadizar and Mariah Meyer and Murat Sincan and Josep M Mercader and Sujin Lee and Jeffrey Haessler and Ha My T Vy and Zhaotong Lin and Nicole D Armstrong and Shaopeng Gu and Noah L Tsao and Leslie A Lange and Ningyuan Wang and Kerri L Wiggins and Stella Trompet and Simin Liu and Ruth J F Loos and Renae Judy and Philip H Schroeder and Natalie R Hasbani and Maxime M Bos and Alanna C Morrison and Rebecca D Jackson and Alexander P Reiner and JoAnn E Manson and Ninad S Chaudhary and Lynn K Carmichael and Yii-Der Ida Chen and Kent D Taylor and Mohsen Ghanbari and Joyce van Meurs and Achilleas N Pitsillides and Bruce M Psaty and Raymond Noordam and Ron Do and Kyong Soo Park and J Wouter Jukema and Maryam Kavousi and Adolfo Correa and Stephen S Rich and Scott M Damrauer and Catherine Hajek and Nam H Cho and Marguerite R Irvin and James S Pankow and Girish N Nadkarni and Robert Sladek and Mark O Goodarzi and Jose C Florez and Daniel I Chasman and Susan R Heckbert and Charles Kooperberg and Josée Dupuis and Rajeev Malhotra and Paul S de Vries and Ching-Ti Liu and Jerome I Rotter and James B Meigs},
doi = {10.1101/2023.07.25.23293180},
year  = {2023},
date = {2023-07-01},
journal = {medRxiv},
abstract = {BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.nnMETHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.nnRESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance (  <5.0×10  ): rs147138607 (intergenic variant between  and  ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32,  =3.6×10  , rs11444867 (intergenic variant near  ) with HR 1.89, 95% CI 1.52 - 2.35,  =9.9×10  , and rs335407 (intergenic variant between  and  ) HR 1.25, 95% CI 1.16 - 1.35,  =1.5×10  . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with  <0.05, and 5 were significant after Bonferroni correction (  <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase (  =1.0×10  ).nnCONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.nnCLINICAL PERSPECTIVE:  We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between  and  ), rs11444867 (intergenic variant near  ), and rs335407 (intergenic variant between  and  ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37279760,
title = {Actionability of unanticipated monogenic disease risks in newborn genomic screening: Findings from the BabySeq Project},
author = {Robert C Green and Nidhi Shah and Casie A Genetti and Timothy Yu and Bethany Zettler and Melissa K Uveges and Ozge Ceyhan-Birsoy and Matthew S Lebo and Stacey Pereira and Pankaj B Agrawal and Richard B Parad and Amy L McGuire and Kurt D Christensen and Talia S Schwartz and Heidi L Rehm and Ingrid A Holm and Alan H Beggs and },
doi = {10.1016/j.ajhg.2023.05.007},
issn = {1537-6605},
year  = {2023},
date = {2023-07-01},
journal = {Am J Hum Genet},
volume = {110},
number = {7},
pages = {1034--1045},
abstract = {Newborn genomic sequencing (NBSeq) to screen for medically important genetic information is of considerable interest but data characterizing the actionability of such findings, and the downstream medical efforts in response to discovery of unanticipated genetic risk variants, are lacking. From a clinical trial of comprehensive exome sequencing in 127 apparently healthy infants and 32 infants in intensive care, we previously identified 17 infants (10.7%) with unanticipated monogenic disease risks (uMDRs). In this analysis, we assessed actionability for each of these uMDRs with a modified ClinGen actionability semiquantitative metric (CASQM) and created radar plots representing degrees of penetrance of the condition, severity of the condition, effectiveness of intervention, and tolerability of intervention. In addition, we followed each of these infants for 3-5 years after disclosure and tracked the medical actions prompted by these findings. All 17 uMDR findings were scored as moderately or highly actionable on the CASQM (mean 9, range: 7-11 on a 0-12 scale) and several distinctive visual patterns emerged on the radar plots. In three infants, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 infants, uMDRs provided risk stratification for future medical surveillance. In 13 infants, uMDRs prompted screening for at-risk family members, three of whom underwent cancer-risk-reducing surgeries. Although assessments of clinical utility and cost-effectiveness will require larger datasets, these findings suggest that large-scale comprehensive sequencing of newborns will reveal numerous actionable uMDRs and precipitate substantial, and in some cases lifesaving, downstream medical care in newborns and their family members.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37382409,
title = {Analysis of brain edema in RHAPSODY},
author = {Riana L Schleicher and Pongpat Vorasayan and Megan E McCabe and Matthew B Bevers and Thomas P Davis and John H Griffin and Archana Hinduja and Ashutosh P Jadhav and Jin-Moo Lee and Robert N Sawyer and Berislav V Zlokovic and Kevin N Sheth and Janel K Fedler and Patrick Lyden and W Taylor Kimberly and },
doi = {10.1177/17474930231187268},
issn = {1747-4949},
year  = {2023},
date = {2023-07-01},
journal = {Int J Stroke},
pages = {17474930231187268},
abstract = {BACKGROUND: Cerebral edema is a secondary complication of acute ischemic stroke, but its time course and imaging markers are not fully understood. Recently, net water uptake (NWU) has been proposed as a novel marker of edema.nnAIMS: Studying the RHAPSODY trial cohort, we sought to characterize the time course of edema and test the hypothesis that NWU provides distinct information when added to traditional markers of cerebral edema after stroke by examining its association with other markers.nnMETHODS: A total of 65 patients had measurable supratentorial ischemic lesions. Patients underwent head computed tomography (CT), brain magnetic resonance imaging (MRI) scans, or both at the baseline visit and after 2, 7, 30, and 90 days following enrollment. CT and MRI scans were used to measure four imaging markers of edema: midline shift (MLS), hemisphere volume ratio (HVR), cerebrospinal fluid (CSF) volume, and NWU using semi-quantitative threshold analysis. Trajectories of the markers were summarized, as available. Correlations of the markers of edema were computed and the markers compared by clinical outcome. Regression models were used to examine the effect of 3K3A-activated protein C (APC) treatment.nnRESULTS: Two measures of mass effect, MLS and HVR, could be measured on all imaging modalities, and had values available across all time points. Accordingly, mass effect reached a maximum level by day 7, normalized by day 30, and then reversed by day 90 for both measures. In the first 2 days after stroke, the change in CSF volume was associated with MLS (ρ = -0.57,  = 0.0001) and HVR (ρ = -0.66,  < 0.0001). In contrast, the change in NWU was not associated with the other imaging markers (all  ⩾ 0.49). While being directionally consistent, we did not observe a difference in the edema markers by clinical outcome. In addition, baseline stroke volume was associated with all markers (MLS ( < 0.001), HVR ( < 0.001), change in CSF volume ( = 0.003)) with the exception of NWU ( = 0.5). Exploratory analysis did not reveal a difference in cerebral edema markers by treatment arm.nnCONCLUSIONS: Existing cerebral edema imaging markers potentially describe two distinct processes, including lesional water concentration (i.e. NWU) and mass effect (MLS, HVR, and CSF volume). These two types of imaging markers may represent distinct aspects of cerebral edema, which could be useful for future trials targeting this process.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37277993,
title = {A model for cis-regulation of transcriptional condensates and gene expression by proximal lncRNAs},
author = {Pradeep Natarajan and Krishna Shrinivas and Arup K Chakraborty},
doi = {10.1016/j.bpj.2023.05.032},
issn = {1542-0086},
year  = {2023},
date = {2023-07-01},
journal = {Biophys J},
volume = {122},
number = {13},
pages = {2757--2772},
abstract = {Long noncoding RNAs (lncRNAs) perform several important functions in cells including cis-regulation of transcription. Barring a few specific cases, the mechanisms underlying transcriptional regulation by lncRNAs remain poorly understood. Transcriptional proteins can form condensates via phase separation at protein-binding loci (BL) on the genome (e.g., enhancers and promoters). lncRNA-coding genes are present at loci in close genomic proximity of these BL and these RNAs can interact with transcriptional proteins via attractive heterotypic interactions mediated by their net charge. Motivated by these observations, we propose that lncRNAs can dynamically regulate transcription in cis via charge-based heterotypic interactions with transcriptional proteins in condensates. To study the consequences of this mechanism, we developed and studied a dynamical phase-field model. We find that proximal lncRNAs can promote condensate formation at the BL. Vicinally localized lncRNA can migrate to the BL to attract more protein because of favorable interaction free energies. However, increasing the distance beyond a threshold leads to a sharp decrease in protein recruitment to the BL. This finding could potentially explain why genomic distances between lncRNA-coding genes and protein-coding genes are conserved across metazoans. Finally, our model predicts that lncRNA transcription can fine-tune transcription from neighboring condensate-controlled genes, repressing transcription from highly expressed genes and enhancing transcription of genes expressed at a low level. This nonequilibrium effect can reconcile conflicting reports that lncRNAs can enhance or repress transcription from proximal genes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37081098,
title = {Nationwide health, socio-economic and genetic predictors of COVID-19 vaccination status in Finland},
author = {Tuomo Hartonen and Bradley Jermy and Hanna Sõnajalg and Pekka Vartiainen and Kristi Krebs and Andrius Vabalas and  and  and Tuija Leino and Hanna Nohynek and Jonas Sivelä and Reedik Mägi and Mark Daly and Hanna M Ollila and Lili Milani and Markus Perola and Samuli Ripatti and Andrea Ganna},
doi = {10.1038/s41562-023-01591-z},
issn = {2397-3374},
year  = {2023},
date = {2023-07-01},
journal = {Nat Hum Behav},
volume = {7},
number = {7},
pages = {1069--1083},
abstract = {Understanding factors associated with COVID-19 vaccination can highlight issues in public health systems. Using machine learning, we considered the effects of 2,890 health, socio-economic and demographic factors in the entire Finnish population aged 30-80 and genome-wide information from 273,765 individuals. The strongest predictors of vaccination status were labour income and medication purchase history. Mental health conditions and having unvaccinated first-degree relatives were associated with reduced vaccination. A prediction model combining all predictors achieved good discrimination (area under the receiver operating characteristic curve, 0.801; 95% confidence interval, 0.799-0.803). The 1% of individuals with the highest predicted risk of not vaccinating had an observed vaccination rate of 18.8%, compared with 90.3% in the study population. We identified eight genetic loci associated with vaccination uptake and derived a polygenic score, which was a weak predictor in an independent subset. Our results suggest that individuals at higher risk of suffering the worst consequences of COVID-19 are also less likely to vaccinate.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37057675,
title = {LHX2 haploinsufficiency causes a variable neurodevelopmental disorder},
author = {Cosima M Schmid and Anne Gregor and Gregory Costain and Chantal F Morel and Lauren Massingham and Jennifer Schwab and Chloé Quélin and Marie Faoucher and Julie Kaplan and Rebecca Procopio and Carol J Saunders and Ana S A Cohen and Gabrielle Lemire and Stephanie Sacharow and Anne O'Donnell-Luria and Ranit Jaron Segal and Jessica Kianmahd Shamshoni and Daniela Schweitzer and Darius Ebrahimi-Fakhari and Kristin Monaghan and Timothy Blake Palculict and Melanie P Napier and Alice Tao and Bertrand Isidor and Kamran Moradkhani and André Reis and Heinrich Sticht and  and Wendy K Chung and Christiane Zweier},
doi = {10.1016/j.gim.2023.100839},
issn = {1530-0366},
year  = {2023},
date = {2023-07-01},
journal = {Genet Med},
volume = {25},
number = {7},
pages = {100839},
abstract = {PURPOSE: LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but it has not been clearly linked to neurodevelopmental disorders (NDDs) to date.nnMETHODS: Through international collaboration, we identified 19 individuals from 18 families with variable neurodevelopmental phenotypes, carrying a small chromosomal deletion, likely gene-disrupting or missense variants in LHX2. Functional consequences of missense variants were investigated in cellular systems.nnRESULTS: Affected individuals presented with developmental and/or behavioral abnormalities, autism spectrum disorder, variable intellectual disability, and microcephaly. We observed nucleolar accumulation for 2 missense variants located within the DNA-binding HOX domain, impaired interaction with co-factor LDB1 for another variant located in the protein-protein interaction-mediating LIM domain, and impaired transcriptional activation by luciferase assay for 4 missense variants.nnCONCLUSION: We implicate LHX2 haploinsufficiency by deletion and likely gene-disrupting variants as causative for a variable NDD. Our findings suggest a loss-of-function mechanism also for likely pathogenic LHX2 missense variants. Together, our observations underscore the importance of LHX2 in the nervous system and for variable neurodevelopmental phenotypes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37345795,
title = {Social Determinants of Health and Cerebral Small Vessel Disease: Is Epigenetics a Key Mediator?},
author = {Livia Parodi and Ernst Mayerhofer and Kaavya Narasimhalu and Nirupama Yechoor and Mary E Comeau and Jonathan Rosand and Carl D Langefeld and Christopher D Anderson},
doi = {10.1161/JAHA.123.029862},
issn = {2047-9980},
year  = {2023},
date = {2023-07-01},
journal = {J Am Heart Assoc},
volume = {12},
number = {13},
pages = {e029862},
abstract = {Cerebral small vessel disease is highly prevalent, particularly in marginalized communities, and its incidence is expected to increase given the aging global population. Cerebral small vessel disease contributes to risk for stroke, vascular cognitive impairment and dementia, late-life depression, and gait disorders. A growing body of evidence suggests that adverse outcomes, including cerebral small vessel disease, caused by traditional cardiovascular risk factors are at least partly mediated by epigenetic changes, some of them already beginning during fetal development. Societal and health care access inequities, summarized under the umbrella term social determinants of health, put a higher burden of cardiovascular risk factors on marginalized populations and expose them to an increased risk for adverse outcomes. Social epigenetics has begun to deliver solid evidence that social determinants of health lead to distinct epigenetic signatures that potentially mediate the biological effect of environmental exposures on cardiovascular risk factors. Here, we provide a review of the most recent advances in the epigenetics of cerebral small vessel disease risk factors and social determinants of health and call for research efforts combining insights from both fields to reach a deeper understanding of the causal pathways, ultimately facilitating discovery of new treatment targets for a disease whose burden is magnified by existing health disparities.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37171500,
title = {Engineered allele substitution at PPARGC1A rs8192678 alters human white adipocyte differentiation, lipogenesis, and PGC-1α content and turnover},
author = {Mi Huang and Melina Claussnitzer and Alham Saadat and Daniel E Coral and Sebastian Kalamajski and Paul W Franks},
doi = {10.1007/s00125-023-05915-6},
issn = {1432-0428},
year  = {2023},
date = {2023-07-01},
journal = {Diabetologia},
volume = {66},
number = {7},
pages = {1289--1305},
abstract = {AIMS/HYPOTHESIS: PPARGC1A encodes peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), a central regulator of energy metabolism and mitochondrial function. A common polymorphism in PPARGC1A (rs8192678, C/T, Gly482Ser) has been associated with obesity and related metabolic disorders, but no published functional studies have investigated direct allele-specific effects in adipocyte biology. We examined whether rs8192678 is a causal variant and reveal its biological function in human white adipose cells.nnMETHODS: We used CRISPR-Cas9 genome editing to perform an allelic switch (C-to-T or T-to-C) at rs8192678 in an isogenic human pre-adipocyte white adipose tissue (hWAs) cell line. Allele-edited single-cell clones were expanded and screened to obtain homozygous T/T (Ser482Ser), C/C (Gly482Gly) and heterozygous C/T (Gly482Ser) isogenic cell populations, followed by functional studies of the allele-dependent effects on white adipocyte differentiation and mitochondrial function.nnRESULTS: After differentiation, the C/C adipocytes were visibly less BODIPY-positive than T/T and C/T adipocytes, and had significantly lower triacylglycerol content. The C allele presented a dose-dependent lowering effect on lipogenesis, as well as lower expression of genes critical for adipogenesis, lipid catabolism, lipogenesis and lipolysis. Moreover, C/C adipocytes had decreased oxygen consumption rate (OCR) at basal and maximal respiration, and lower ATP-linked OCR. We determined that these effects were a consequence of a C-allele-driven dysregulation of PGC-1α protein content, turnover rate and transcriptional coactivator activity.nnCONCLUSIONS/INTERPRETATION: Our data show allele-specific causal effects of the rs8192678 variant on adipogenic differentiation. The C allele confers lower levels of PPARGC1A mRNA and PGC-1α protein, as well as disrupted dynamics of PGC-1α turnover and activity, with downstream effects on cellular differentiation and mitochondrial function. Our study provides the first experimentally deduced insights on the effects of rs8192678 on adipocyte phenotype.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37259866,
title = {New Approaches for Targeting PCSK9: Small-Interfering Ribonucleic Acid and Genome Editing},
author = {Reindert F Oostveen and Amit V Khera and Sekar Kathiresan and Erik S G Stroes and Kevin Fitzgerald and Matthew J Harms and Benjamin L Oakes and John J P Kastelein},
doi = {10.1161/ATVBAHA.122.317963},
issn = {1524-4636},
year  = {2023},
date = {2023-07-01},
journal = {Arterioscler Thromb Vasc Biol},
volume = {43},
number = {7},
pages = {1081--1092},
abstract = {There is overwhelming clinical and genetic evidence supporting the concept that low-density-lipoprotein cholesterol should be as low as possible for as long as possible in patients at very high cardiovascular risk. Despite the wide availability of effective lipid-lowering therapies, the majority of patients still fail to reach guideline-based lipid goals. Advances in novel approaches targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) through small-interfering RNA and genome editing hold the potential to bridge this gap, by offering long-acting alternatives, which may overcome adherence and other challenges in the current chronic care model. In this review, we discuss the history of targeting PCSK9 with the use of mRNA and small-interfering ribonucleic acid. We also shed light on targeting PCSK9 with genome editing, including discussion of the VERVE-101 clustered regularly interspaced short palindromic repeats-base editing medicine currently being evaluated in a clinical trial and others in development.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36987712,
title = {H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome},
author = {Nicholas Borja and Paulo Borjas-Mendoza and Stephanie Bivona and LéShon Peart and Joanna Gonzalez and Brittney Keira Johnson and Shengru Guo and Roman Yusupov and  and Guney Bademci and Mustafa Tekin},
doi = {10.1002/ajmg.a.63193},
issn = {1552-4833},
year  = {2023},
date = {2023-07-01},
journal = {Am J Med Genet A},
volume = {191},
number = {7},
pages = {1911--1916},
abstract = {Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37460956,
title = {A causal effects of gut microbiota in the development of migraine},
author = {Qiang He and Wenjing Wang and Yang Xiong and Chuanyuan Tao and Lu Ma and Junpeng Ma and Chao You and },
doi = {10.1186/s10194-023-01609-x},
issn = {1129-2377},
year  = {2023},
date = {2023-07-01},
journal = {J Headache Pain},
volume = {24},
number = {1},
pages = {90},
abstract = {BACKGROUND: The causal association between the gut microbiome and the development of migraine and its subtypes remains unclear.nnMETHODS: The single nucleotide polymorphisms concerning gut microbiome were retrieved from the gene-wide association study (GWAS) of the MiBioGen consortium. The summary statistics datasets of migraine, migraine with aura (MA), and migraine without aura (MO) were obtained from the GWAS meta-analysis of the International Headache Genetics Consortium (IHGC) and FinnGen consortium. Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness.nnRESULTS: In IHGC datasets, ten, five, and nine bacterial taxa were found to have a causal association with migraine, MA, and MO, respectively, (IVW, all P < 0.05). Genus.Coprococcus3 and genus.Anaerotruncus were validated in FinnGen datasets. Nine, twelve, and seven bacterial entities were identified for migraine, MA, and MO, respectively. The causal association still exists in family.Bifidobacteriaceae and order.Bifidobacteriales for migraine and MO after FDR correction. The heterogeneity and pleiotropy analyses confirmed the robustness of IVW results.nnCONCLUSION: Our study demonstrates that gut microbiomes may exert causal effects on migraine, MA, and MO. We provide novel evidence for the dysfunction of the gut-brain axis on migraine. Future study is required to verify the relationship between gut microbiome and the risk of migraine and its subtypes and illustrate the underlying mechanism between them.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37503195,
title = {Improved Protocol for Reproducible Human Cortical Organoids Reveals Early Alterations in Metabolism with  Mutations},
author = {Taylor Bertucci and Kathryn R Bowles and Steven Lotz and Le Qi and Katherine Stevens and Susan K Goderie and Susan Borden and Laura Maria Oja and Keith Lane and Ryan Lotz and Hailey Lotz and Rebecca Chowdhury and Shona Joy and Brigitte L Arduini and David C Butler and Michael Miller and Heide Baron and Carl Alexander Sandhof and M Catarina Silva and Stephen J Haggarty and Celeste M Karch and Daniel H Geschwind and Alison M Goate and Sally Temple},
doi = {10.1101/2023.07.11.548571},
year  = {2023},
date = {2023-07-01},
journal = {bioRxiv},
abstract = {Cerebral cortical-enriched organoids derived from human pluripotent stem cells (hPSCs) are valuable models for studying neurodevelopment, disease mechanisms, and therapeutic development. However, recognized limitations include the high variability of organoids across hPSC donor lines and experimental replicates. We report a 96-slitwell method for efficient, scalable, reproducible cortical organoid production. When hPSCs were cultured with controlled-release FGF2 and an SB431542 concentration appropriate for their  /  expression level, organoid cortical patterning and reproducibility were significantly improved. Well-patterned organoids included 16 neuronal and glial subtypes by single cell RNA sequencing (scRNA-seq), frequent neural progenitor rosettes and robust BCL11B+ and TBR1+ deep layer cortical neurons at 2 months by immunohistochemistry. In contrast, poorly-patterned organoids contain mesendoderm-related cells, identifiable by negative QC markers including  . Using this improved protocol, we demonstrate increased sensitivity to study the impact of different  mutations from patients with frontotemporal dementia (FTD), revealing early changes in key metabolic pathways.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37379836,
title = {Polygenic risk prediction: why and when out-of-sample prediction R can exceed SNP-based heritability},
author = {Xiaotong Wang and Alicia Walker and Joana A Revez and Guiyan Ni and Mark J Adams and Andrew M McIntosh and  and Peter M Visscher and Naomi R Wray},
doi = {10.1016/j.ajhg.2023.06.006},
issn = {1537-6605},
year  = {2023},
date = {2023-07-01},
journal = {Am J Hum Genet},
volume = {110},
number = {7},
pages = {1207--1215},
abstract = {In polygenic score (PGS) analysis, the coefficient of determination (R) is a key statistic to evaluate efficacy. R is the proportion of phenotypic variance explained by the PGS, calculated in a cohort that is independent of the genome-wide association study (GWAS) that provided estimates of allelic effect sizes. The SNP-based heritability (h, the proportion of total phenotypic variances attributable to all common SNPs) is the theoretical upper limit of the out-of-sample prediction R. However, in real data analyses R has been reported to exceed h, which occurs in parallel with the observation that h estimates tend to decline as the number of cohorts being meta-analyzed increases. Here, we quantify why and when these observations are expected. Using theory and simulation, we show that if heterogeneities in cohort-specific h exist, or if genetic correlations between cohorts are less than one, h estimates can decrease as the number of cohorts being meta-analyzed increases. We derive conditions when the out-of-sample prediction R will be greater than h and show the validity of our derivations with real data from a binary trait (major depression) and a continuous trait (educational attainment). Our research calls for a better approach to integrating information from multiple cohorts to address issues of between-cohort heterogeneity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36711496,
title = {Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases},
author = {Kai Yuan and Ryan J Longchamps and Antonio F Pardinas and Mingrui Yu and Tzu-Ting Chen and Shu-Chin Lin and Yu Chen and Max Lam and Ruize Liu and Yan Xia and Zhenglin Guo and Wenzhao Shi and Chengguo Shen and  and Mark J Daly and Benjamine Neale and Yen-Chen Anne Feng and Yen-Feng Lin and Chia-Yen Chen and Michael O'Donovan and Tian Ge and Hailiang Huang},
doi = {10.1101/2023.01.07.23284293},
year  = {2023},
date = {2023-07-01},
journal = {medRxiv},
abstract = {Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European descent has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and computationally efficient method for cross-population fine-mapping, which builds on the single-population fine-mapping framework, Sum of Single Effects (SuSiE). SuSiEx integrates data from an arbitrary number of ancestries, explicitly models population-specific allele frequencies and LD patterns, accounts for multiple causal variants in a genomic region, and can be applied to GWAS summary statistics when individual-level data is unavailable. We comprehensively evaluated SuSiEx using simulations, a range of quantitative traits measured in both UK Biobank and Taiwan Biobank, and schizophrenia GWAS across East Asian and European ancestries. In all evaluations, SuSiEx fine-mapped more association signals, produced smaller credible sets and higher posterior inclusion probability (PIP) for putative causal variants, and retained population-specific causal variants.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37534745,
title = {Multilevel barriers and facilitators to widespread use of preconception carrier screening in the United States},
author = {Leland E Hull and Kelsey Flannery and Anjali Kaimal and Karen Sepucha and Heidi L Rehm and Jennifer S Haas},
doi = {10.1016/j.gim.2023.100946},
issn = {1530-0366},
year  = {2023},
date = {2023-07-01},
journal = {Genet Med},
volume = {25},
number = {12},
pages = {100946},
abstract = {PURPOSE: Although preconception reproductive genetic carrier screening (RGCS) is preferred to screening during pregnancy, population-wide preconception screening is not routinely performed in the United States. We explored the multilevel barriers to the widespread adoption of preconception RGCS in the United States via key informant interviews.nnMETHODS: Semi-structured virtual video interviews were conducted with 29 informants with a breadth of professional expertise between May and October 2022. Data collection and qualitative analyses were guided by the Consolidated Framework for Implementation Research and socioecological model. Analysis focused on identifying barriers to delivering preconception RGCS at and across different levels of health care and exploring potential facilitators of preconception RGCS delivery.nnRESULTS: Barriers to preconception RGCS were identified at the levels of test characteristics, patients and couples, clinicians and care teams, and the external health care and policy environments. Across the different levels of care delivery, 3 themes of barriers emerged: (1) fragmentation and inconsistencies hinder care delivery, (2) gaps in knowledge, misconceptions, and uncertainties about RGCS are pervasive, and (3) expanding preconception RGCS in the diverse US population presents unique implementation challenges. Potential solutions were detailed by informants.nnCONCLUSION: Identifying individual and thematic barriers to preconception RGCS delivery may help to define strategies to alleviate obstacles.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37345823,
title = {Birth Weight Is Associated With Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Outcomes in Adulthood},
author = {Art Schuermans and Tetsushi Nakao and Yunfeng Ruan and Satoshi Koyama and Zhi Yu and Md Mesbah Uddin and Sara Haidermota and Whitney Hornsby and Adam J Lewandowski and Alexander G Bick and Abhishek Niroula and Siddhartha Jaiswal and Benjamin L Ebert and Pradeep Natarajan and Michael C Honigberg},
doi = {10.1161/JAHA.123.030220},
issn = {2047-9980},
year  = {2023},
date = {2023-07-01},
journal = {J Am Heart Assoc},
volume = {12},
number = {13},
pages = {e030220},
abstract = {Background High and low birth weight are independently associated with increased cardiovascular disease risk in adulthood. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with preleukemic somatic mutations, predicts incident cardiovascular disease independent of traditional cardiovascular risk factors. Whether birth weight predicts development of CHIP later in life is unknown. Methods and Results A total of 221 047 adults enrolled in the UK Biobank with whole exome sequences and self-reported birth weight were analyzed. Of those, 22 030 (11.5%) had low (<2.5 kg) and 29 292 (14.7%) high birth weight (>4.0 kg). CHIP prevalence was higher among participants with low (6.0%, =0.049) and high (6.3%, <0.001) versus normal birth weight (5.7%, ref.). Multivariable-adjusted logistic regression analyses demonstrated that each 1-kg increase in birth weight was associated with a 3% increased risk of CHIP (odds ratio, 1.03 [95% CI, 1.00-1.06]; =0.04), driven by a stronger association observed between birth weight and  CHIP (odds ratio, 1.04 per 1-kg increase [95% CI, 1.01-1.08]; =0.02). Mendelian randomization analyses supported a causal relationship of longer gestational age at delivery with  CHIP. Multivariable Cox regression demonstrated that CHIP was independently and additively associated with incident cardiovascular disease or death across birth weight groups, with highest absolute risks in those with CHIP plus high or low birth weight. Conclusions Higher birth weight is associated with increased risk of developing CHIP in midlife, especially  CHIP. These findings identify a novel risk factor for CHIP and provide insights into the relationships among early-life environment, CHIP, cancer, and cardiovascular disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36581494,
title = {Excitatory Dysfunction Drives Network and Calcium Handling Deficits in 16p11.2 Duplication Schizophrenia Induced Pluripotent Stem Cell-Derived Neurons},
author = {Euan Parnell and Lorenza Culotta and Marc P Forrest and Hiba A Jalloul and Blair L Eckman and Daniel D Loizzo and Katherine K E Horan and Marc Dos Santos and Nicolas H Piguel and Derek J C Tai and Hanwen Zhang and Tracy S Gertler and Dina Simkin and Alan R Sanders and Michael E Talkowski and Pablo V Gejman and Evangelos Kiskinis and Jubao Duan and Peter Penzes},
doi = {10.1016/j.biopsych.2022.11.005},
issn = {1873-2402},
year  = {2023},
date = {2023-07-01},
journal = {Biol Psychiatry},
volume = {94},
number = {2},
pages = {153--163},
abstract = {BACKGROUND: Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human induced pluripotent stem cell-derived neurons (iNs) has emerged as a promising strategy. Copy number variants confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing the risk 14.5-fold.nnMETHODS: To dissect the contribution of induced excitatory neurons (iENs) versus GABAergic (gamma-aminobutyric acidergic) neurons (iGNs) to SCZ pathophysiology, we induced iNs from CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 isogenic and SCZ patient-derived induced pluripotent stem cells and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures.nnRESULTS: In iEN/iGN cocultures, neuronal firing and synchrony were reduced at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for iENs. Moreover, isogenic iENs showed reduced dendrite length and deficits in calcium handling. iENs from 16p11.2 duplication-carrying patients with SCZ displayed overlapping deficits in network synchrony, dendrite outgrowth, and calcium handling. Transcriptomic analysis of both iEN cohorts revealed molecular markers of disease related to the glutamatergic synapse, neuroarchitecture, and calcium regulation.nnCONCLUSIONS: Our results indicate the presence of 16p11.2 duplication-dependent alterations in SCZ patient-derived iENs. Transcriptomics and cellular phenotyping reveal overlap between isogenic and patient-derived iENs, suggesting a central role of glutamatergic, morphological, and calcium dysregulation in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers. Our results support network synchrony and calcium handling as outcomes directly linked to this genetic risk variant.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37429925,
title = {Author Correction: Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death},
author = {Alicia B Byrne and Peer Arts and Thuong T Ha and Karin S Kassahn and Lynn S Pais and Anne O'Donnell-Luria and  and Milena Babic and Mahalia S B Frank and Jinghua Feng and Paul Wang and David M Lawrence and Leila Eshraghi and Luis Arriola and John Toubia and Hung Nguyen and  and George McGillivray and Jason Pinner and Fiona McKenzie and Rebecca Morrow and Jill Lipsett and Nick Manton and T Yee Khong and Lynette Moore and Jan E Liebelt and Andreas W Schreiber and Sarah L King-Smith and Tristan S E Hardy and Matilda R Jackson and Christopher P Barnett and Hamish S Scott},
doi = {10.1038/s41591-023-02487-1},
issn = {1546-170X},
year  = {2023},
date = {2023-07-01},
journal = {Nat Med},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37419095,
title = {Response to Li and Hopper},
author = {Nina Mars and Joni V Lindbohm and Pietro Della Briotta Parolo and Elisabeth Widén and Jaakko Kaprio and Aarno Palotie and  and Samuli Ripatti},
doi = {10.1016/j.ajhg.2023.05.016},
issn = {1537-6605},
year  = {2023},
date = {2023-07-01},
journal = {Am J Hum Genet},
volume = {110},
number = {7},
pages = {1224--1225},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37414900,
title = {A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease},
author = {Aniruddh P Patel and Minxian Wang and Yunfeng Ruan and Satoshi Koyama and Shoa L Clarke and Xiong Yang and Catherine Tcheandjieu and Saaket Agrawal and Akl C Fahed and Patrick T Ellinor and  and Philip S Tsao and Yan V Sun and Kelly Cho and Peter W F Wilson and Themistocles L Assimes and David A van Heel and Adam S Butterworth and Krishna G Aragam and Pradeep Natarajan and Amit V Khera},
doi = {10.1038/s41591-023-02429-x},
issn = {1546-170X},
year  = {2023},
date = {2023-07-01},
journal = {Nat Med},
volume = {29},
number = {7},
pages = {1793--1803},
abstract = {Identification of individuals at highest risk of coronary artery disease (CAD)-ideally before onset-remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable risk stratification, reflecting the substantial inherited component to CAD risk. Here we develop a new and significantly improved polygenic score for CAD, termed GPS, that incorporates genome-wide association data across five ancestries for CAD (>269,000 cases and >1,178,000 controls) and ten CAD risk factors. GPS strongly associated with prevalent CAD (odds ratio per standard deviation 2.14, 95% confidence interval 2.10-2.19, P < 0.001) in UK Biobank participants of European ancestry, identifying 20.0% of the population with 3-fold increased risk and conversely 13.9% with 3-fold decreased risk as compared with those in the middle quintile. GPS was also associated with incident CAD events (hazard ratio per standard deviation 1.73, 95% confidence interval 1.70-1.76, P < 0.001), identifying 3% of healthy individuals with risk of future CAD events equivalent to those with existing disease and significantly improving risk discrimination and reclassification. Across multiethnic, external validation datasets inclusive of 33,096, 124,467, 16,433 and 16,874 participants of African, European, Hispanic and South Asian ancestry, respectively, GPS demonstrated increased strength of associations across all ancestries and outperformed all available previously published CAD polygenic scores. These data contribute a new GPS for CAD to the field and provide a generalizable framework for how large-scale integration of genetic association data for CAD and related traits from diverse populations can meaningfully improve polygenic risk prediction.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37454163,
title = {Decoding information about cognitive health from the brainwaves of sleep},
author = {Noor Adra and Lisa W Dümmer and Luis Paixao and Ryan A Tesh and Haoqi Sun and Wolfgang Ganglberger and Mike Westmeijer and Madalena Da Silva Cardoso and Anagha Kumar and Elissa Ye and Jonathan Henry and Sydney S Cash and Erin Kitchener and Catherine L Leveroni and Rhoda Au and Jonathan Rosand and Joel Salinas and Alice D Lam and Robert J Thomas and M Brandon Westover},
doi = {10.1038/s41598-023-37128-7},
issn = {2045-2322},
year  = {2023},
date = {2023-07-01},
journal = {Sci Rep},
volume = {13},
number = {1},
pages = {11448},
abstract = {Sleep electroencephalogram (EEG) signals likely encode brain health information that may identify individuals at high risk for age-related brain diseases. Here, we evaluate the correlation of a previously proposed brain age biomarker, the "brain age index" (BAI), with cognitive test scores and use machine learning to develop and validate a series of new sleep EEG-based indices, termed "sleep cognitive indices" (SCIs), that are directly optimized to correlate with specific cognitive scores. Three overarching cognitive processes were examined: total, fluid (a measure of cognitive processes involved in reasoning-based problem solving and susceptible to aging and neuropathology), and crystallized cognition (a measure of cognitive processes involved in applying acquired knowledge toward problem-solving). We show that SCI decoded information about total cognition (Pearson's r = 0.37) and fluid cognition (Pearson's r = 0.56), while BAI correlated only with crystallized cognition (Pearson's r = - 0.25). Overall, these sleep EEG-derived biomarkers may provide accessible and clinically meaningful indicators of neurocognitive health.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37285119,
title = {Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy},
author = {Jaakko S Tyrmi and Tea Kaartokallio and A Inkeri Lokki and Tiina Jääskeläinen and Eija Kortelainen and Sanni Ruotsalainen and Juha Karjalainen and Samuli Ripatti and Anna Kivioja and Triin Laisk and Johannes Kettunen and Anneli Pouta and Katja Kivinen and Eero Kajantie and Seppo Heinonen and Juha Kere and Hannele Laivuori and },
doi = {10.1001/jamacardio.2023.1312},
issn = {2380-6591},
year  = {2023},
date = {2023-07-01},
journal = {JAMA Cardiol},
volume = {8},
number = {7},
pages = {674--683},
abstract = {IMPORTANCE: A genetic contribution to preeclampsia susceptibility has been established but is still incompletely understood.nnOBJECTIVE: To disentangle the underlying genetic architecture of preeclampsia and preeclampsia or other maternal hypertension during pregnancy with a genome-wide association study (GWAS) of hypertensive disorders of pregnancy.nnDESIGN, SETTING, AND PARTICIPANTS: This GWAS included meta-analyses in maternal preeclampsia and a combination phenotype encompassing maternal preeclampsia and preeclampsia or other maternal hypertensive disorders. Two overlapping phenotype groups were selected for examination, namely, preeclampsia and preeclampsia or other maternal hypertension during pregnancy. Data from the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC, 1990-2011), Finnish FinnGen project (1964-2019), Estonian Biobank (1997-2019), and the previously published InterPregGen consortium GWAS were combined. Individuals with preeclampsia or other maternal hypertension during pregnancy and control individuals were selected from the cohorts based on relevant International Classification of Diseases codes. Data were analyzed from July 2020 to February 2023.nnEXPOSURES: The association of a genome-wide set of genetic variants and clinical risk factors was analyzed for the 2 phenotypes.nnRESULTS: A total of 16 743 women with prior preeclampsia and 15 200 with preeclampsia or other maternal hypertension during pregnancy were obtained from FINNPEC, FinnGen, Estonian Biobank, and the InterPregGen consortium study (respective mean [SD] ages at diagnosis: 30.3 [5.5], 28.7 [5.6], 29.7 [7.0], and 28 [not available] years). The analysis found 19 genome-wide significant associations, 13 of which were novel. Seven of the novel loci harbor genes previously associated with blood pressure traits (NPPA, NPR3, PLCE1, TNS2, FURIN, RGL3, and PREX1). In line with this, the 2 study phenotypes showed genetic correlation with blood pressure traits. In addition, novel risk loci were identified in the proximity of genes involved in the development of placenta (PGR, TRPC6, ACTN4, and PZP), remodeling of uterine spiral arteries (NPPA, NPPB, NPR3, and ACTN4), kidney function (PLCE1, TNS2, ACTN4, and TRPC6), and maintenance of proteostasis in pregnancy serum (PZP).nnCONCLUSIONS AND RELEVANCE: The findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid35451673,
title = {Validity of the SNAP-IV For ADHD Assessment in South African Children With Neurodevelopmental Disorders},
author = {Michal R Zieff and Michelle Hoogenhout and Emma Eastman and Björn U Christ and Alice Galvin and Victoria de Menil and Amina Abubakar and Charles R Newton and Elise Robinson and Kirsten A Donald},
doi = {10.1007/s10803-022-05530-1},
issn = {1573-3432},
year  = {2023},
date = {2023-07-01},
journal = {J Autism Dev Disord},
volume = {53},
number = {7},
pages = {2851--2862},
abstract = {This study investigated the psychometric properties of the Swanson, Nolan, and Pelham ADHD Rating Scale (SNAP-IV) in a sample of South African children with neurodevelopmental disorders (n = 201), primarily Autism Spectrum Disorder and Intellectual Disability. We conducted a confirmatory factor analysis to inspect the two-factor structure of the SNAP-IV. We also calculated ordinal coefficient alpha to estimate internal consistency. Fit statistics for the two-factor model approached acceptable levels. The model fit improved slightly after removing an item related to spoken language. The subscales had acceptable internal consistencies. Findings partially support the use of the SNAP-IV in this group of children. However, there are limitations to its performance in this population likely related to the presence of neurodevelopmental disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37534744,
title = {The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change},
author = {Heidi L Rehm and Joseph T Alaimo and Swaroop Aradhya and Pinar Bayrak-Toydemir and Hunter Best and Rhonda Brandon and Jillian G Buchan and Elizabeth C Chao and Elaine Chen and Jacob Clifford and Ana S A Cohen and Laura K Conlin and Soma Das and Kyle W Davis and Daniela Del Gaudio and Florencia Del Viso and Christina DiVincenzo and Marcia Eisenberg and Lucia Guidugli and Monia B Hammer and Steven M Harrison and Kathryn E Hatchell and Lindsay Havens Dyer and Lily U Hoang and James M Holt and Vaidehi Jobanputra and Izabela D Karbassi and Hutton M Kearney and Melissa A Kelly and Jacob M Kelly and Michelle L Kluge and Timothy Komala and Paul Kruszka and Lynette Lau and Matthew S Lebo and Christian R Marshall and Dianalee McKnight and Kirsty McWalter and Yan Meng and Narasimhan Nagan and Christian S Neckelmann and Nir Neerman and Zhiyv Niu and Vitoria K Paolillo and Sarah A Paolucci and Denise Perry and Tina Pesaran and Kelly Radtke and Kristen J Rasmussen and Kyle Retterer and Carol J Saunders and Elizabeth Spiteri and Christine Stanley and Anna Szuto and Ryan J Taft and Isabelle Thiffault and Brittany C Thomas and Amanda Thomas-Wilson and Erin Thorpe and Timothy J Tidwell and Meghan C Towne and Hana Zouk and },
doi = {10.1016/j.gim.2023.100947},
issn = {1530-0366},
year  = {2023},
date = {2023-07-01},
journal = {Genet Med},
pages = {100947},
abstract = {PURPOSE: Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact.nnMETHODS: Rates of inconclusive results due to VUS were collected from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 - 2021.nnRESULTS: We found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared to MGPs (32.6%; p<0.0001). For MGPs, the rate of inconclusive results correlated with panel size. The use of trios reduced inconclusive rates (18.9% vs 27.6%; p<0.001) whereas the use of GS compared to ES had no impact (22.2% vs 22.6%; p=ns).nnCONCLUSION: The high rate of VUS observed in diagnostic MGP testing warrants examining current variant reporting practices. We propose several approaches to reduce reported VUS rates, while directing clinician resources towards important VUS follow-up.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37519474,
title = {Life After Mild Traumatic Brain Injury: Widespread Structural Brain Changes Associated With Psychological Distress Revealed With Multimodal Magnetic Resonance Imaging},
author = {Francesca Sibilia and Rachel M Custer and Andrei Irimia and Farshid Sepehrband and Arthur W Toga and Ryan P Cabeen and },
doi = {10.1016/j.bpsgos.2022.03.004},
issn = {2667-1743},
year  = {2023},
date = {2023-07-01},
journal = {Biol Psychiatry Glob Open Sci},
volume = {3},
number = {3},
pages = {374--385},
abstract = {BACKGROUND: Traumatic brain injury (TBI) can alter brain structure and lead to onset of persistent neuropsychological symptoms. This study investigates the relationship between brain injury and psychological distress after mild TBI using multimodal magnetic resonance imaging.nnMETHODS: A total of 89 patients with mild TBI from the TRACK-TBI (Transforming Research and Clinical Knowledge in Traumatic Brain Injury) pilot study were included. Subscales of the Brief Symptoms Inventory 18 for depression, anxiety, and somatization were used as outcome measures of psychological distress approximately 6 months after the traumatic event. Glasgow Coma Scale scores were used to evaluate recovery. Magnetic resonance imaging data were acquired within 2 weeks after injury. Perivascular spaces (PVSs) were segmented using an enhanced PVS segmentation method, and the volume fraction was calculated for the whole brain and white matter regions. Cortical thickness and gray matter structures volumes were calculated in FreeSurfer; diffusion imaging indices and multifiber tracts were extracted using the Quantitative Imaging Toolkit. The analysis was performed considering age, sex, intracranial volume, educational attainment, and improvement level upon discharge as covariates.nnRESULTS: PVS fractions in the posterior cingulate, fusiform, and postcentral areas were found to be associated with somatization symptoms. Depression, anxiety, and somatization symptoms were associated with the cortical thickness of the frontal-opercularis and occipital pole, putamen and amygdala volumes, and corticospinal tract and superior thalamic radiation. Analyses were also performed on the two hemispheres separately to explore lateralization.nnCONCLUSIONS: This study shows how PVS, cortical, and microstructural changes can predict the onset of depression, anxiety, and somatization symptoms in patients with mild TBI.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37308786,
title = {Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program},
author = {Derek Klarin and Poornima Devineni and Anoop K Sendamarai and Anthony R Angueira and Sarah E Graham and Ying H Shen and Michael G Levin and James P Pirruccello and Ida Surakka and Purushotham R Karnam and Tanmoy Roychowdhury and Yanming Li and Minxian Wang and Krishna G Aragam and Kaavya Paruchuri and Verena Zuber and Gabrielle E Shakt and Noah L Tsao and Renae L Judy and Ha My T Vy and Shefali S Verma and Daniel J Rader and Ron Do and Joseph E Bavaria and Girish N Nadkarni and Marylyn D Ritchie and  and Stephen Burgess and Dong-Chuan Guo and Patrick T Ellinor and Scott A LeMaire and Dianna M Milewicz and Cristen J Willer and Pradeep Natarajan and Philip S Tsao and Saiju Pyarajan and Scott M Damrauer},
doi = {10.1038/s41588-023-01420-z},
issn = {1546-1718},
year  = {2023},
date = {2023-07-01},
journal = {Nat Genet},
volume = {55},
number = {7},
pages = {1106--1115},
abstract = {The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37492105,
title = {Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins},
author = {Natalie DeForest and Babu Kavitha and Siqi Hu and Roi Isaac and Lynne Krohn and Minxian Wang and Xiaomi Du and Camila De Arruda Saldanha and Jenny Gylys and Edoardo Merli and Ruben Abagyan and Laeya Najmi and Viswanathan Mohan and  and  and Jason Flannick and Gina M Peloso and Philip L S M Gordts and Sven Heinz and Aimee M Deaton and Amit V Khera and Jerrold Olefsky and Venkatesan Radha and Amit R Majithia},
doi = {10.1016/j.xgen.2023.100339},
issn = {2666-979X},
year  = {2023},
date = {2023-07-01},
journal = {Cell Genom},
volume = {3},
number = {7},
pages = {100339},
abstract = {Loss-of-function mutations in hepatocyte nuclear factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare, protein-coding  variant, most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding  variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found that ∼1:5 rare protein-coding  variants in the general population cause molecular gain of function (GOF), increasing the transcriptional activity of HNF1A by up to 50% and conferring protection from type 2 diabetes (odds ratio [OR] = 0.77, p = 0.007). Increased hepatic expression of  promoted a pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including  and . In summary, ∼1:300 individuals carry a GOF variant in  that protects carriers from diabetes but enhances hepatic secretion of atherogenic lipoproteins.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37400552,
title = {Author Correction: Clonal haematopoiesis and risk of chronic liver disease},
author = {Waihay J Wong and Connor Emdin and Alexander G Bick and Seyedeh M Zekavat and Abhishek Niroula and James P Pirruccello and Laura Dichtel and Gabriel Griffin and Md Mesbah Uddin and Christopher J Gibson and Veronica Kovalcik and Amy E Lin and Marie E McConkey and Amelie Vromman and Rob S Sellar and Peter G Kim and Mridul Agrawal and Joshua Weinstock and Michelle T Long and Bing Yu and Rajarshi Banerjee and Rowan C Nicholls and Andrea Dennis and Matt Kelly and Po-Ru Loh and Steve McCarroll and Eric Boerwinkle and Ramachandran S Vasan and Siddhartha Jaiswal and Andrew D Johnson and Raymond T Chung and Kathleen Corey and Daniel Levy and Christie Ballantyne and  and Benjamin L Ebert and Pradeep Natarajan},
doi = {10.1038/s41586-023-06375-z},
issn = {1476-4687},
year  = {2023},
date = {2023-07-01},
journal = {Nature},
volume = {619},
number = {7970},
pages = {E47},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37402854,
title = {Bipolar disorder-iPSC derived neural progenitor cells exhibit dysregulation of store-operated Ca entry and accelerated differentiation},
author = {Tristen Hewitt and Begüm Alural and Manali Tilak and Jennifer Wang and Natalina Becke and Ellis Chartley and Melissa Perreault and Stephen J Haggarty and Steven D Sheridan and Roy H Perlis and Nina Jones and Nikolaos Mellios and Jasmin Lalonde},
doi = {10.1038/s41380-023-02152-6},
issn = {1476-5578},
year  = {2023},
date = {2023-07-01},
journal = {Mol Psychiatry},
abstract = {While most of the efforts to uncover mechanisms contributing to bipolar disorder (BD) focused on phenotypes at the mature neuron stage, little research has considered events that may occur during earlier timepoints of neurodevelopment. Further, although aberrant calcium (Ca) signaling has been implicated in the etiology of this condition, the possible contribution of store-operated Ca entry (SOCE) is not well understood. Here, we report Ca and developmental dysregulations related to SOCE in BD patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells (BD-NPCs) and cortical-like glutamatergic neurons. First, using a Ca re-addition assay we found that BD-NPCs and neurons had attenuated SOCE. Intrigued by this finding, we then performed RNA-sequencing and uncovered a unique transcriptome profile in BD-NPCs suggesting accelerated neurodifferentiation. Consistent with these results, we measured a slower rate of proliferation, increased neurite outgrowth, and decreased size in neurosphere formations with BD-NPCs. Also, we observed decreased subventricular areas in developing BD cerebral organoids. Finally, BD NPCs demonstrated high expression of the let-7 family while BD neurons had increased miR-34a, both being microRNAs previously implicated in neurodevelopmental deviations and BD etiology. In summary, we present evidence supporting an accelerated transition towards the neuronal stage in BD-NPCs that may be indicative of early pathophysiological features of the disorder.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37133451,
title = {Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease},
author = {Sumudu S C Amarasekera and Daniella H Hock and Nicole J Lake and Sarah E Calvo and Sabine W Grønborg and Emma I Krzesinski and David J Amor and Michael C Fahey and Cas Simons and Flemming Wibrand and Vamsi K Mootha and Monkol Lek and Sebastian Lunke and Zornitza Stark and Elsebet Østergaard and John Christodoulou and David R Thorburn and David A Stroud and Alison G Compton},
doi = {10.1093/hmg/ddad069},
issn = {1460-2083},
year  = {2023},
date = {2023-07-01},
journal = {Hum Mol Genet},
volume = {32},
number = {15},
pages = {2441--2454},
abstract = {MRPL39 encodes one of 52 proteins comprising the large subunit of the mitochondrial ribosome (mitoribosome). In conjunction with 30 proteins in the small subunit, the mitoribosome synthesizes the 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) system encoded by mitochondrial Deoxyribonucleic acid (DNA). We used multi-omics and gene matching to identify three unrelated individuals with biallelic variants in MRPL39 presenting with multisystem diseases with severity ranging from lethal, infantile-onset (Leigh syndrome spectrum) to milder with survival into adulthood. Clinical exome sequencing of known disease genes failed to diagnose these patients; however quantitative proteomics identified a specific decrease in the abundance of large but not small mitoribosomal subunits in fibroblasts from the two patients with severe phenotype. Re-analysis of exome sequencing led to the identification of candidate single heterozygous variants in mitoribosomal genes MRPL39 (both patients) and MRPL15. Genome sequencing identified a shared deep intronic MRPL39 variant predicted to generate a cryptic exon, with transcriptomics and targeted studies providing further functional evidence for causation. The patient with the milder disease was homozygous for a missense variant identified through trio exome sequencing. Our study highlights the utility of quantitative proteomics in detecting protein signatures and in characterizing gene-disease associations in exome-unsolved patients. We describe Relative Complex Abundance analysis of proteomics data, a sensitive method that can identify defects in OXPHOS disorders to a similar or greater sensitivity to the traditional enzymology. Relative Complex Abundance has potential utility for functional validation or prioritization in many hundreds of inherited rare diseases where protein complex assembly is disrupted.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37474567,
title = {Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals},
author = {Ludovica Montanucci and David Lewis-Smith and Ryan L Collins and Lisa-Marie Niestroj and Shridhar Parthasarathy and Julie Xian and Shiva Ganesan and Marie Macnee and Tobias Brünger and Rhys H Thomas and Michael Talkowski and  and Ingo Helbig and Costin Leu and Dennis Lal},
doi = {10.1038/s41467-023-39539-6},
issn = {2041-1723},
year  = {2023},
date = {2023-07-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {4392},
abstract = {Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36883380,
title = {Gut microbiota-associated metabolites and risk of ischemic stroke in REGARDS},
author = {Zsuzsanna Ament and Amit Patki and Varun M Bhave and Ninad S Chaudhary and Ana-Lucia Garcia Guarniz and Naruchorn Kijpaisalratana and Suzanne E Judd and Mary Cushman and D Leann Long and M Ryan Irvin and W Taylor Kimberly},
doi = {10.1177/0271678X231162648},
issn = {1559-7016},
year  = {2023},
date = {2023-07-01},
journal = {J Cereb Blood Flow Metab},
volume = {43},
number = {7},
pages = {1089--1098},
abstract = {Several metabolite markers are independently associated with incident ischemic stroke. However, prior studies have not accounted for intercorrelated metabolite networks. We used exploratory factor analysis (EFA) to determine if metabolite factors were associated with incident ischemic stroke. Metabolites (n = 162) were measured in a case-control cohort nested in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, which included 1,075 ischemic stroke cases and 968 random cohort participants. Cox models were adjusted for age, gender, race, and age-race interaction (base model) and further adjusted for the Framingham stroke risk factors (fully adjusted model). EFA identified fifteen metabolite factors, each representing a well-defined metabolic pathway. Of these, factor 3, a gut microbiome metabolism factor, was associated with an increased risk of stroke in the base (hazard ratio per one-unit standard deviation, HR = 1.23; 95%CI = 1.15-1.31; P = 1.98 × 10) and fully adjusted models (HR = 1.13; 95%CI = 1.06-1.21; P = 4.49 × 10). The highest tertile had a 45% increased risk relative to the lowest (HR = 1.45; 95%CI = 1.25-1.70; P = 2.24 × 10). Factor 3 was also associated with the Southern diet pattern, a dietary pattern previously linked to increased stroke risk in REGARDS (β = 0.11; 95%CI = 0.03-0.18; P = 8.75 × 10). These findings highlight the role of diet and gut microbial metabolism in relation to incident ischemic stroke.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37489815,
title = {Genetic variation supports a causal role for valproate in prevention of ischemic stroke},
author = {Ernst Mayerhofer and Livia Parodi and Kaavya Narasimhalu and Stefan Wolking and Andreas Harloff and Marios K Georgakis and Jonathan Rosand and Christopher D Anderson},
doi = {10.1177/17474930231190259},
issn = {1747-4949},
year  = {2023},
date = {2023-07-01},
journal = {Int J Stroke},
pages = {17474930231190259},
abstract = {BACKGROUND: Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions.nnAIMS: We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke.nnMETHODS: We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. As replication, we tested found associations in an independent cohort of valproate users of the Mass General Brigham Biobank.nnRESULTS: Among 2150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12 year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per 1 standard deviation (SD), 95% confidence interval (CI) (3.45, 8.11)). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (hazard ratio (HR) per 1 SD 0.73, 95% CI (0.58, 0.91)) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%,  trend = 0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per 1 SD 0.53, 95% CI (0.32, 0.86)) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs 13/71, 18.3%,  trend = 0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users ( = 0.61), suggesting minimal pleiotropy. In 1241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per 1 SD 0.77, 95% CI (0.61, 0.97)).nnCONCLUSION: These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention.nnDATA ACCESS STATEMENT: UK Biobank participant data are available after approval of a research proposal. The weights of the used genetic scores are available in the Supplemental Tables.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37547012,
title = {PheMIME: An Interactive Web App and Knowledge Base for Phenome-Wide, Multi-Institutional Multimorbidity Analysis},
author = {Siwei Zhang and Nick Strayer and Tess Vessels and Karmel Choi and Geoffrey W Wang and Yajing Li and Cosmin A Bejan and Ryan S Hsi and Alexander G Bick and Digna R Velez Edwards and Michael R Savona and Elizabeth J Philips and Jill Pulley and Wesley H Self and Wilkins Consuelo Hopkins and Dan M Roden and Jordan W Smoller and Douglas M Ruderfer and Yaomin Xu},
doi = {10.1101/2023.07.23.23293047},
year  = {2023},
date = {2023-07-01},
journal = {medRxiv},
abstract = {MOTIVATION: Multimorbidity, characterized by the simultaneous occurrence of multiple diseases in an individual, is an increasing global health concern, posing substantial challenges to healthcare systems. Comprehensive understanding of disease-disease interactions and intrinsic mechanisms behind multimorbidity can offer opportunities for innovative prevention strategies, targeted interventions, and personalized treatments. Yet, there exist limited tools and datasets that characterize multimorbidity patterns across different populations. To bridge this gap, we used large-scale electronic health record (EHR) systems to develop the Phenome-wide Multi-Institutional Multimorbidity Explorer (PheMIME), which facilitates research in exploring and comparing multimorbidity patterns among multiple institutions, potentially leading to the discovery of novel and robust disease associations and patterns that are interoperable across different systems and organizations.nnRESULTS: PheMIME integrates summary statistics from phenome-wide analyses of disease multimorbidities. These are currently derived from three major institutions: Vanderbilt University Medical Center, Mass General Brigham, and the UK Biobank. PheMIME offers interactive exploration of multimorbidity through multi-faceted visualization. Incorporating an enhanced version of associationSubgraphs, PheMIME enables dynamic analysis and inference of disease clusters, promoting the discovery of multimorbidity patterns. Once a disease of interest is selected, the tool generates interactive visualizations and tables that users can delve into multimorbidities or multimorbidity networks within a single system or compare across multiple systems. The utility of PheMIME is demonstrated through a case study on schizophrenia.nnAVAILABILITY AND IMPLEMENTATION: The PheMIME knowledge base and web application are accessible at https://prod.tbilab.org/PheMIME/ . A comprehensive tutorial, including a use-case example, is available at https://prod.tbilab.org/PheMIME_supplementary_materials/ . Furthermore, the source code for PheMIME can be freely downloaded from https://github.com/tbilab/PheMIME .nnDATA AVAILABILITY STATEMENT: The data underlying this article are available in the article and in its online web application or supplementary material.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37519470,
title = {Sensitive Periods for the Effect of Childhood Adversity on DNA Methylation: Updated Results From a Prospective, Longitudinal Study},
author = {Alexandre A Lussier and Yiwen Zhu and Brooke J Smith and Andrew J Simpkin and Andrew D A C Smith and Matthew J Suderman and Esther Walton and Caroline L Relton and Kerry J Ressler and Erin C Dunn},
doi = {10.1016/j.bpsgos.2022.04.002},
issn = {2667-1743},
year  = {2023},
date = {2023-07-01},
journal = {Biol Psychiatry Glob Open Sci},
volume = {3},
number = {3},
pages = {567--571},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37492099,
title = {Discovering cellular programs of intrinsic and extrinsic drivers of metabolic traits using LipocyteProfiler},
author = {Samantha Laber and Sophie Strobel and Josep M Mercader and Hesam Dashti and Felipe R C Dos Santos and Phil Kubitz and Maya Jackson and Alina Ainbinder and Julius Honecker and Saaket Agrawal and Garrett Garborcauskas and David R Stirling and Aaron Leong and Katherine Figueroa and Nasa Sinnott-Armstrong and Maria Kost-Alimova and Giacomo Deodato and Alycen Harney and Gregory P Way and Alham Saadat and Sierra Harken and Saskia Reibe-Pal and Hannah Ebert and Yixin Zhang and Virtu Calabuig-Navarro and Elizabeth McGonagle and Adam Stefek and Josée Dupuis and Beth A Cimini and Hans Hauner and Miriam S Udler and Anne E Carpenter and Jose C Florez and Cecilia Lindgren and Suzanne B R Jacobs and Melina Claussnitzer},
doi = {10.1016/j.xgen.2023.100346},
issn = {2666-979X},
year  = {2023},
date = {2023-07-01},
journal = {Cell Genom},
volume = {3},
number = {7},
pages = {100346},
abstract = {A primary obstacle in translating genetic associations with disease into therapeutic strategies is elucidating the cellular programs affected by genetic risk variants and effector genes. Here, we introduce LipocyteProfiler, a cardiometabolic-disease-oriented high-content image-based profiling tool that enables evaluation of thousands of morphological and cellular profiles that can be systematically linked to genes and genetic variants relevant to cardiometabolic disease. We show that LipocyteProfiler allows surveillance of diverse cellular programs by generating rich context- and process-specific cellular profiles across hepatocyte and adipocyte cell-state transitions. We use LipocyteProfiler to identify known and novel cellular mechanisms altered by polygenic risk of metabolic disease, including insulin resistance, fat distribution, and the polygenic contribution to lipodystrophy. LipocyteProfiler paves the way for large-scale forward and reverse deep phenotypic profiling in lipocytes and provides a framework for the unbiased identification of causal relationships between genetic variants and cellular programs relevant to human disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37547003,
title = { as a target for splice modulation to prevent somatic CAG repeat expansion in Huntington's disease},
author = {Zachariah L McLean and Dadi Gao and Kevin Correia and Jennie C L Roy and Shota Shibata and Iris N Farnum and Zoe Valdepenas-Mellor and Manasa Rapuru and Elisabetta Morini and Jayla Ruliera and Tammy Gillis and Diane Lucente and Benjamin P Kleinstiver and Jong-Min Lee and Marcy E MacDonald and Vanessa C Wheeler and Ricardo Mouro Pinto and James F Gusella},
doi = {10.1101/2023.07.25.550489},
year  = {2023},
date = {2023-07-01},
journal = {bioRxiv},
abstract = {Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder whose motor, cognitive, and behavioral manifestations are caused by an expanded, somatically unstable CAG repeat in the first exon of  that lengthens a polyglutamine tract in huntingtin. Genome-wide association studies (GWAS) have revealed DNA repair genes that influence the age-at-onset of HD and implicate somatic CAG repeat expansion as the primary driver of disease timing. To prevent the consequent neuronal damage, small molecule splice modulators (e.g., branaplam) that target  to reduce the levels of huntingtin are being investigated as potential HD therapeutics. We found that the effectiveness of the splice modulators can be influenced by genetic variants, both at  and other genes where they promote pseudoexon inclusion. Surprisingly, in a novel hTERT-immortalized retinal pigment epithelial cell (RPE1) model for assessing CAG repeat instability, these drugs also reduced the rate of  CAG expansion. We determined that the splice modulators also affect the expression of the mismatch repair gene  , a known modifier of HD age-at-onset. Genome editing at specific  and  sequences using CRISPR-Cas9 nuclease confirmed that branaplam suppresses CAG expansion by promoting the inclusion of a pseudoexon in  , making splice modulation of  a potential strategy for delaying HD onset. Comparison with another splice modulator, risdiplam, suggests that other genes affected by these splice modulators also influence CAG instability and might provide additional therapeutic targets.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37502935,
title = {The Cardiovascular Impact and Genetics of Pericardial Adiposity},
author = {Joel T Rämö and Shinwan Kany and Cody R Hou and Samuel F Friedman and Carolina Roselli and Victor Nauffal and Satoshi Koyama and Juha Karjalainen and  and Mahnaz Maddah and Aarno Palotie and Patrick T Ellinor and James P Pirruccello},
doi = {10.1101/2023.07.16.23292729},
year  = {2023},
date = {2023-07-01},
journal = {medRxiv},
abstract = {BACKGROUND: While previous studies have reported associations of pericardial adipose tissue (PAT) with cardiovascular diseases such as atrial fibrillation and coronary artery disease, they have been limited in sample size or drawn from selected populations. Additionally, the genetic determinants of PAT remain largely unknown. We aimed to evaluate the association of PAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of PAT in a large population cohort.nnMETHODS: A deep learning model was trained to quantify PAT area from four-chamber magnetic resonance images in the UK Biobank using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. A genome-wide association study was performed, and a polygenic score (PGS) for PAT was examined in 453,733 independent FinnGen study participants.nnRESULTS: A total of 44,725 UK Biobank participants (51.7% female, mean [SD] age 64.1 [7.7] years) were included. PAT was positively associated with male sex (β = +0.76 SD in PAT), age (  = 0.15), body mass index (BMI;  = 0.47) and waist-to-hip ratio (  = 0.55) (P < 1×10  ). PAT was more elevated in prevalent heart failure (β = +0.46 SD units) and type 2 diabetes (β = +0.56) than in coronary artery disease (β = +0.22) or AF (β = +0.18). PAT was associated with incident heart failure (HR = 1.29 per +1 SD in PAT [95% CI 1.17-1.43]) and type 2 diabetes (HR = 1.63 [1.51-1.76]) during a mean 3.2 (±1.5) years of follow-up; the associations remained significant when controlling for BMI. We identified 5 novel genetic loci for PAT and implicated transcriptional regulators of adipocyte morphology and brown adipogenesis (  ,  and  ) and regulators of visceral adiposity (  and  ). The PAT PGS was associated with T2D, heart failure, coronary artery disease and atrial fibrillation in FinnGen (ORs 1.03-1.06 per +1 SD in PGS, P < 2×10  ).nnCONCLUSIONS: PAT shares genetic determinants with abdominal adiposity and is an independent predictor of incident type 2 diabetes and heart failure.nnCLINICAL PERSPECTIVE: What is new? In a large, prospective and uniformly phenotyped cohort, pericardial adipose tissue was independently predictive of incident heart failure and type 2 diabetes when adjusted for body mass index.In contrast, pericardial adipose tissue was not independently predictive of atrial fibrillation.A genome-wide association study of pericardial adipose tissue identified five novel loci, implicating genes influencing adipocyte morphology, brown-like adipose tissue differentiation and abdominal adiposity. What are the clinical implications? Pericardial adipose tissue accumulation may reflect a metabolically unhealthy adiposity phenotype similarly to abdominal visceral adiposity.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37363945,
title = {Clinical and Genetic Atrial Fibrillation Risk and Discrimination of Cardioembolic From Noncardioembolic Stroke},
author = {Lu-Chen Weng and Shaan Khurshid and Sophia Gunn and Ludovic Trinquart and Kathryn L Lunetta and Huichun Xu and  and Emelia J Benjamin and Patrick T Ellinor and Christopher D Anderson and Steven A Lubitz},
doi = {10.1161/STROKEAHA.122.041533},
issn = {1524-4628},
year  = {2023},
date = {2023-07-01},
journal = {Stroke},
volume = {54},
number = {7},
pages = {1777--1785},
abstract = {BACKGROUND: Stroke is a leading cause of death and disability worldwide. Atrial fibrillation (AF) is a common cause of stroke but may not be detectable at the time of stroke. We hypothesized that an AF polygenic risk score (PRS) can discriminate between cardioembolic stroke and noncardioembolic strokes.nnMETHODS: We evaluated AF and stroke risk in 26 145 individuals of European descent from the Stroke Genetics Network case-control study. AF genetic risk was estimated using 3 recently developed PRS methods (LDpred-funct-inf, sBayesR, and PRS-CS) and 2 previously validated PRSs. We performed logistic regression of each AF PRS on AF status and separately cardioembolic stroke, adjusting for clinical risk score (CRS), imputation group, and principal components. We calculated model discrimination of AF and cardioembolic stroke using the concordance statistic (c-statistic) and compared c-statistics using 2000-iteration bootstrapping. We also assessed reclassification of cardioembolic stroke with the addition of PRS to either CRS or a modified CHADS-VASc score alone.nnRESULTS: Each AF PRS was significantly associated with AF and with cardioembolic stroke after adjustment for CRS. Addition of each AF PRS significantly improved discrimination as compared with CRS alone (<0.01). When combined with the CRS, both PRS-CS and LDpred scores discriminated both AF and cardioembolic stroke (c-statistic 0.84 for AF; 0.74 for cardioembolic stroke) better than 3 other PRS scores (<0.01). Using PRS-CS PRS and CRS in combination resulted in more appropriate reclassification of stroke events as compared with CRS alone (event reclassification [net reclassification indices]=14% [95% CI, 10%-18%]; nonevent reclassification [net reclassification indices]=17% [95% CI, 15%-0.19%]) or the modified CHADS-VASc score (net reclassification indices=11% [95% CI, 7%-15%]; net reclassification indices=14% [95% CI, 12%-16%]) alone.nnCONCLUSIONS: Addition of polygenic risk of AF to clinical risk factors modestly improves the discrimination of cardioembolic from noncardioembolic strokes, as well as reclassification of stroke subtype. Polygenic risk of AF may be a useful biomarker for identifying strokes caused by AF.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37301908,
title = {Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality},
author = {Asmundur Oddsson and Patrick Sulem and Gardar Sveinbjornsson and Gudny A Arnadottir and Valgerdur Steinthorsdottir and Gisli H Halldorsson and Bjarni A Atlason and Gudjon R Oskarsson and Hannes Helgason and Henriette Svarre Nielsen and David Westergaard and Juha M Karjalainen and Hildigunnur Katrinardottir and Run Fridriksdottir and Brynjar O Jensson and Vinicius Tragante and Egil Ferkingstad and Hakon Jonsson and Sigurjon A Gudjonsson and Doruk Beyter and Kristjan H S Moore and Helga B Thordardottir and Snaedis Kristmundsdottir and Olafur A Stefansson and Solbritt Rantapää-Dahlqvist and Ida Elken Sonderby and Maria Didriksen and Pernilla Stridh and Jan Haavik and Laufey Tryggvadottir and Oleksandr Frei and G Bragi Walters and Ingrid Kockum and Henrik Hjalgrim and Thorunn A Olafsdottir and Geir Selbaek and Mette Nyegaard and Christian Erikstrup and Thorsten Brodersen and Saedis Saevarsdottir and Tomas Olsson and Kaspar Rene Nielsen and Asgeir Haraldsson and Mie Topholm Bruun and Thomas Folkmann Hansen and  and Thora Steingrimsdottir and Rikke Louise Jacobsen and Rolv T Lie and Srdjan Djurovic and Lars Alfredsson and Aitzkoa Lopez de Lapuente Portilla and Soren Brunak and Pall Melsted and Bjarni V Halldorsson and Jona Saemundsdottir and Olafur Th Magnusson and Leonid Padyukov and Karina Banasik and Thorunn Rafnar and Johan Askling and Lars Klareskog and Ole Birger Pedersen and Gisli Masson and Alexandra Havdahl and Bjorn Nilsson and Ole A Andreassen and Mark Daly and Sisse Rye Ostrowski and Ingileif Jonsdottir and Hreinn Stefansson and Hilma Holm and Agnar Helgason and Unnur Thorsteinsdottir and Kari Stefansson and Daniel F Gudbjartsson},
doi = {10.1038/s41467-023-38951-2},
issn = {2041-1723},
year  = {2023},
date = {2023-06-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {3453},
abstract = {Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37218590,
title = {Identification of White Matter Hyperintensities in Routine Emergency Department Visits Using Portable Bedside Magnetic Resonance Imaging},
author = {Adam de Havenon and Nethra R Parasuram and Anna L Crawford and Mercy H Mazurek and Isha R Chavva and Vineetha Yadlapalli and Juan E Iglesias and Matthew S Rosen and Guido J Falcone and Seyedmehdi Payabvash and Gordon Sze and Richa Sharma and Steven J Schiff and Basmah Safdar and Charles Wira and William T Kimberly and Kevin N Sheth},
doi = {10.1161/JAHA.122.029242},
issn = {2047-9980},
year  = {2023},
date = {2023-06-01},
journal = {J Am Heart Assoc},
volume = {12},
number = {11},
pages = {e029242},
abstract = {Background White matter hyperintensity (WMH) on magnetic resonance imaging (MRI) of the brain is associated with vascular cognitive impairment, cardiovascular disease, and stroke. We hypothesized that portable magnetic resonance imaging (pMRI) could successfully identify WMHs and facilitate doing so in an unconventional setting. Methods and Results In a retrospective cohort of patients with both a conventional 1.5 Tesla MRI and pMRI, we report Cohen's kappa (κ) to measure agreement for detection of moderate to severe WMH (Fazekas ≥2). In a subsequent prospective observational study, we enrolled adult patients with a vascular risk factor being evaluated in the emergency department for a nonstroke complaint and measured WMH using pMRI. In the retrospective cohort, we included 33 patients, identifying 16 (49.5%) with WMH on conventional MRI. Between 2 raters evaluating pMRI, the interrater agreement on WMH was strong (κ=0.81), and between 1 rater for conventional MRI and the 2 raters for pMRI, intermodality agreement was moderate (κ=0.66, 0.60). In the prospective cohort we enrolled 91 individuals (mean age, 62.6 years; 53.9% men; 73.6% with hypertension), of which 58.2% had WMHs on pMRI. Among 37 Black and Hispanic individuals, the Area Deprivation Index was higher (versus White, 51.8±12.9 versus 37.9±11.9; <0.001). Among 81 individuals who did not have a standard-of-care MRI in the preceding year, we identified WMHs in 43 of 81 (53.1%). Conclusions Portable, low-field imaging could be useful for identifying moderate to severe WMHs. These preliminary results introduce a novel role for pMRI outside of acute care and the potential role for pMRI to reduce disparities in neuroimaging.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36717286,
title = {A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study},
author = {Noah M Hahn and Michael A O'Donnell and Jason A Efstathiou and Marianna Zahurak and Gary L Rosner and Jeff Smith and Max R Kates and Trinity J Bivalacqua and Phuoc T Tran and Daniel Y Song and Alex S Baras and Andres Matoso and Woonyoung Choi and Kellie N Smith and Drew M Pardoll and Luigi Marchionni and Bridget McGuire and Mary Grace Phelan and Burles A Johnson and Tanya O'Neal and David J McConkey and Tracy L Rose and Marc Bjurlin and Emerson A Lim and Charles G Drake and James M McKiernan and Israel Deutsch and Christopher B Anderson and Donald L Lamm and Daniel M Geynisman and Elizabeth R Plimack and Mark A Hallman and Eric M Horwitz and Essel Al-Saleem and David Y T Chen and Richard E Greenberg and Alexander Kutikov and Gordon Guo and Timothy A Masterson and Nabil Adra and Hristos Z Kaimakliotis},
doi = {10.1016/j.eururo.2023.01.017},
issn = {1873-7560},
year  = {2023},
date = {2023-06-01},
journal = {Eur Urol},
volume = {83},
number = {6},
pages = {486--494},
abstract = {BACKGROUND: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients.nnOBJECTIVE: To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT).nnDESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 1 trial was conducted at community and academic sites.nnINTERVENTION: Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only).nnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates.nnRESULTS AND LIMITATIONS: Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients.nnCONCLUSIONS: D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches.nnPATIENT SUMMARY: Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37071471,
title = {Obesity-induced inflammation exacerbates clonal hematopoiesis},
author = {Santhosh Kumar Pasupuleti and Baskar Ramdas and Sarah S Burns and Lakshmi Reddy Palam and Rahul Kanumuri and Ramesh Kumar and Taruni Reddy Pandhiri and Utpal P Dave and Nanda Kumar Yellapu and Xinyu Zhou and Chi Zhang and George E Sandusky and Zhi Yu and Michael C Honigberg and Alexander G Bick and Gabriel K Griffin and Abhishek Niroula and Benjamin L Ebert and Sophie Paczesny and Pradeep Natarajan and Reuben Kapur},
doi = {10.1172/JCI163968},
issn = {1558-8238},
year  = {2023},
date = {2023-06-01},
journal = {J Clin Invest},
volume = {133},
number = {11},
abstract = {Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis of indeterminate potential (CHIP) is frequent in aging and involves the expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, the risk factors that contribute to CHIP-associated clonal hematopoiesis (CH) are poorly understood. Obesity induces a proinflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data for 47,466 individuals with validated CHIP in the UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in the waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1, and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and that a proinflammatory state could potentiate the progression of CHIP to more significant hematologic neoplasia. The calcium channel blockers nifedipine and SKF-96365, either alone or in combination with metformin, MCC950, or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP-mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in individuals with obesity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37296118,
title = {Language network lateralization is reflected throughout the macroscale functional organization of cortex},
author = {Loïc Labache and Tian Ge and B T Thomas Yeo and Avram J Holmes},
doi = {10.1038/s41467-023-39131-y},
issn = {2041-1723},
year  = {2023},
date = {2023-06-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {3405},
abstract = {Hemispheric specialization is a fundamental feature of human brain organization. However, it is not yet clear to what extent the lateralization of specific cognitive processes may be evident throughout the broad functional architecture of cortex. While the majority of people exhibit left-hemispheric language dominance, a substantial minority of the population shows reverse lateralization. Using twin and family data from the Human Connectome Project, we provide evidence that atypical language dominance is associated with global shifts in cortical organization. Individuals with atypical language organization exhibit corresponding hemispheric differences in the macroscale functional gradients that situate discrete large-scale networks along a continuous spectrum, extending from unimodal through association territories. Analyses reveal that both language lateralization and gradient asymmetries are, in part, driven by genetic factors. These findings pave the way for a deeper understanding of the origins and relationships linking population-level variability in hemispheric specialization and global properties of cortical organization.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37248299,
title = {Polygenic prediction of preeclampsia and gestational hypertension},
author = {Michael C Honigberg and Buu Truong and Raiyan R Khan and Brenda Xiao and Laxmi Bhatta and Ha My T Vy and Rafael F Guerrero and Art Schuermans and Margaret Sunitha Selvaraj and Aniruddh P Patel and Satoshi Koyama and So Mi Jemma Cho and Shamsudheen Karuthedath Vellarikkal and Mark Trinder and Sarah M Urbut and Kathryn J Gray and Ben M Brumpton and Snehal Patil and Sebastian Zöllner and Mariah C Antopia and Richa Saxena and Girish N Nadkarni and Ron Do and Qi Yan and Itsik Pe'er and Shefali Setia Verma and Rajat M Gupta and David M Haas and Hilary C Martin and David A van Heel and Triin Laisk and Pradeep Natarajan},
doi = {10.1038/s41591-023-02374-9},
issn = {1546-170X},
year  = {2023},
date = {2023-06-01},
journal = {Nat Med},
volume = {29},
number = {6},
pages = {1540--1549},
abstract = {Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR-CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36808743,
title = {Circadian Rest-Activity Rhythms, Delirium Risk, and Progression to Dementia},
author = {Lei Gao and Peng Li and Nicole Gaykova and Xi Zheng and Chenlu Gao and Jacqueline M Lane and Richa Saxena and Frank A J L Scheer and Martin K Rutter and Oluwaseun Akeju and Kun Hu},
doi = {10.1002/ana.26617},
issn = {1531-8249},
year  = {2023},
date = {2023-06-01},
journal = {Ann Neurol},
volume = {93},
number = {6},
pages = {1145--1157},
abstract = {OBJECTIVE: Delirium is a complex neurocognitive syndrome suspected to be bidirectionally linked to dementia. Circadian rhythm disturbances likely contribute to dementia pathogenesis, but whether these disturbances are related to delirium risk and progression to all-cause dementia is unknown.nnMETHODS: We analyzed continuous actigraphy data from 53,417 middle-aged or older UK Biobank participants during a median 5 years of follow-up. Four measures were used to characterize the 24-hour daily rest-activity rhythms (RARs): normalized amplitude, acrophase representing the peak activity time, interdaily stability, and intradaily variability (IV) for fragmentation of the rhythm. Cox proportional hazards models examined whether RARs predicted incident delirium (n = 551) and progression to dementia (n = 61).nnRESULTS: Suppressed 24-hour amplitude, lowest (Q1) versus highest (Q4) quartile (hazard ratio [HR] = 1.94, 95% confidence interval [CI] = 1.53-2.46, p < 0.001), and more fragmented (higher IV: HR = 1.49, 95% CI = 1.18-1.88, p < 0.001) rhythms predicted higher delirium risk, after adjusting for age, sex, education, cognitive performance, sleep duration/disturbances, and comorbidities. In those free from dementia, each hour of delayed acrophase was associated with delirium risk (HR = 1.13, 95% CI = 1.04-1.23, p = 0.003). Suppressed 24-hour amplitude was associated with increased risk of progression from delirium to new onset dementia (HR = 1.31, 95% CI = 1.03-1.67, p = 0.03 for each 1-standard deviation decrease).nnINTERPRETATION: Twenty-four-hour daily RAR suppression, fragmentation, and potentially delayed acrophase were associated with delirium risk. Subsequent progression to dementia was more likely in delirium cases with suppressed rhythms. The presence of RAR disturbances before delirium and prior to progression to dementia suggests that these disturbances may predict higher risk and be involved in early disease pathogenesis. ANN NEUROL 2023;93:1145-1157.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37188555,
title = {Frequent questions and responses on the 2022 lipoprotein(a) consensus statement of the European Atherosclerosis Society},
author = {Florian Kronenberg and Samia Mora and Erik S G Stroes and Brian A Ference and Benoit J Arsenault and Lars Berglund and Marc R Dweck and Marlys L Koschinsky and Gilles Lambert and François Mach and Catherine J McNeal and Patrick M Moriarty and Pradeep Natarajan and Børge G Nordestgaard and Klaus G Parhofer and Salim S Virani and Arnold von Eckardstein and Gerald F Watts and Jane K Stock and Kausik K Ray and Lale S Tokgözoğlu and Alberico L Catapano},
doi = {10.1016/j.atherosclerosis.2023.04.012},
issn = {1879-1484},
year  = {2023},
date = {2023-06-01},
journal = {Atherosclerosis},
volume = {374},
pages = {107--120},
abstract = {In 2022, the European Atherosclerosis Society (EAS) published a new consensus statement on lipoprotein(a) [Lp(a)], summarizing current knowledge about its causal association with atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. One of the novelties of this statement is a new risk calculator showing how Lp(a) influences lifetime risk for ASCVD and that global risk may be underestimated substantially in individuals with high or very high Lp(a) concentration. The statement also provides practical advice on how knowledge about Lp(a) concentration can be used to modulate risk factor management, given that specific and highly effective mRNA-targeted Lp(a)-lowering therapies are still in clinical development. This advice counters the attitude: "Why should I measure Lp(a) if I can't lower it?". Subsequent to publication, questions have arisen relating to how the recommendations of this statement impact everyday clinical practice and ASCVD management. This review addresses 30 of the most frequently asked questions about Lp(a) epidemiology, its contribution to cardiovascular risk, Lp(a) measurement, risk factor management and existing therapeutic options.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36639294,
title = {Emulating a Target Trial of Dynamic Treatment Strategies for Major Depressive Disorder Using Data From the STAR∗D Randomized Trial},
author = {Alejandro G Szmulewicz and Kerollos N Wanis and Roy H Perlis and Sonia Hernández-Díaz and Dost Öngür and Miguel A Hernán},
doi = {10.1016/j.biopsych.2022.09.028},
issn = {1873-2402},
year  = {2023},
date = {2023-06-01},
journal = {Biol Psychiatry},
volume = {93},
number = {12},
pages = {1127--1136},
abstract = {BACKGROUND: Clinical guidelines recommend adding a second drug for patients with major depressive disorder who have a partial response and switching antidepressants for those who show no response or intolerance. This guidelines-based strategy was compared with other strategies for the management of unresponsive depression.nnMETHODS: A total of 1436 individuals experiencing treatment failure with citalopram and still requiring antidepressant therapy were identified in the STAR∗D (Sequenced Treatment Alternatives to Relieve Depression) trial. A (hypothetical) target trial was then designed and emulated. The following strategies for decision making were compared: sequential monotherapy, sequential dual non-selective serotonin reuptake inhibitor therapy (SD), and a guidelines-based strategy. The primary outcome was symptomatic remission defined as a Hamilton Depression Rating Scale score ≤7 or 2 consecutive scores ≤5 on the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated. Secondary outcomes were serious events (hospitalizations, suicide, and mortality). Inverse probability weighting was used to control for possible confounding.nnRESULTS: A total of 971 patients were eligible for our emulation. Patients initiating SD had the lowest levels of depression at baseline. The estimated 9-month probability of remission was 43.5% for the sequential monotherapy group, 47.6% for the SD group, and 53.2% for the guidelines-based strategy group. Compared with the sequential monotherapy group, the difference in 9-month probability of remission was -4.2% (95% CI, -15.6 to 4.6) for the SD group and -9.7% (-19.3 to 1.9) for the guidelines-based strategy group. The 9-month relative risks of remission were 1.09 (0.90 to 1.38) and 1.22 (0.96 to 1.46), respectively. Results were consistent across sensitivity analyses. The 9-month relative risks of serious events were 0.77 (0.38 to 1.40) and 0.62 (0.33 to 1.00), respectively.nnCONCLUSIONS: Using the guidelines-based strategy was associated with an increased probability of remission and a lower risk of serious adverse events. The potential implications are substantial given the large number of patients experiencing treatment failure to antidepressants.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37333378,
title = {Identifying modifiable comorbidities of schizophrenia by integrating electronic health records and polygenic risk},
author = {Tess Vessels and Nicholas Strayer and Karmel W Choi and Hyunjoon Lee and Siwei Zhang and Lide Han and Theodore J Morley and Jordan W Smoller and Yaomin Xu and Douglas M Ruderfer},
doi = {10.1101/2023.06.01.23290057},
year  = {2023},
date = {2023-06-01},
journal = {medRxiv},
abstract = {Patients with schizophrenia have substantial comorbidity contributing to reduced life expectancy of 10-20 years. Identifying which comorbidities might be modifiable could improve rates of premature mortality in this population. We hypothesize that conditions that frequently co-occur but lack shared genetic risk with schizophrenia are more likely to be products of treatment, behavior, or environmental factors and therefore potentially modifiable. To test this hypothesis, we calculated phenome-wide comorbidity from electronic health records (EHR) in 250,000 patients in each of two independent health care institutions (Vanderbilt University Medical Center and Mass General Brigham) and association with schizophrenia polygenic risk scores (PRS) across the same phenotypes (phecodes) in linked biobanks. Comorbidity with schizophrenia was significantly correlated across institutions (r = 0.85) and consistent with prior literature. After multiple test correction, there were 77 significant phecodes comorbid with schizophrenia. Overall, comorbidity and PRS association were highly correlated (r = 0.55, p = 1.29×10  ), however, 36 of the EHR identified comorbidities had significantly equivalent schizophrenia PRS distributions between cases and controls. Fifteen of these lacked any PRS association and were enriched for phenotypes known to be side effects of antipsychotic medications (e.g., "movement disorders", "convulsions", "tachycardia") or other schizophrenia related factors such as from smoking ("bronchitis") or reduced hygiene (e.g., "diseases of the nail") highlighting the validity of this approach. Other phenotypes implicated by this approach where the contribution from shared common genetic risk with schizophrenia was minimal included tobacco use disorder, diabetes, and dementia. This work demonstrates the consistency and robustness of EHR-based schizophrenia comorbidities across independent institutions and with the existing literature. It identifies comorbidities with an absence of shared genetic risk indicating other causes that might be more modifiable and where further study of causal pathways could improve outcomes for patients.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37291107,
title = {South Asian medical cohorts reveal strong founder effects and high rates of homozygosity},
author = {Jeffrey D Wall and J Fah Sathirapongsasuti and Ravi Gupta and Asif Rasheed and Radha Venkatesan and Saurabh Belsare and Ramesh Menon and Sameer Phalke and Anuradha Mittal and John Fang and Deepak Tanneeru and Manjari Deshmukh and Akshi Bassi and Jacqueline Robinson and Ruchi Chaudhary and Sakthivel Murugan and Zameer Ul-Asar and Imran Saleem and Unzila Ishtiaq and Areej Fatima and Saqib Shafi Sheikh and Shahid Hameed and Mohammad Ishaq and Syed Zahed Rasheed and Fazal-Ur-Rehman Memon and Anjum Jalal and Shahid Abbas and Philippe Frossard and Christian Fuchsberger and Lukas Forer and Sebastian Schoenherr and Qixin Bei and Tushar Bhangale and Jennifer Tom and Santosh Gopi Krishna Gadde and Priya B V and Naveen Kumar Naik and Minxian Wang and Pui-Yan Kwok and Amit V Khera and B R Lakshmi and Adam S Butterworth and Rajiv Chowdhury and John Danesh and Emanuele di Angelantonio and Aliya Naheed and Vinay Goyal and Rukmini M Kandadai and Hrishikesh Kumar and Rupam Borgohain and Adreesh Mukherjee and Pettarusp M Wadia and Ravi Yadav and Soaham Desai and Niraj Kumar and Atanu Biswas and Pramod Kumar Pal and Uday B Muthane and Shymal K Das and Vedam L Ramprasad and Prashanth L Kukkle and Somasekar Seshagiri and Sekar Kathiresan and Arkasubhra Ghosh and V Mohan and Danish Saleheen and Eric W Stawiski and Andrew S Peterson},
doi = {10.1038/s41467-023-38766-1},
issn = {2041-1723},
year  = {2023},
date = {2023-06-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {3377},
abstract = {The benefits of large-scale genetic studies for healthcare of the populations studied are well documented, but these genetic studies have traditionally ignored people from some parts of the world, such as South Asia. Here we describe whole genome sequence (WGS) data from 4806 individuals recruited from the healthcare delivery systems of Pakistan, India and Bangladesh, combined with WGS from 927 individuals from isolated South Asian populations. We characterize population structure in South Asia and describe a genotyping array (SARGAM) and imputation reference panel that are optimized for South Asian genomes. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of rare homozygotes that reach 100 times that seen in outbred populations. Founder effects increase the power to associate functional variants with disease processes and make South Asia a uniquely powerful place for population-scale genetic studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37425772,
title = {Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study},
author = {Yuxuan Wang and Margaret Sunitha Selvaraj and Xihao Li and Zilin Li and Jacob A Holdcraft and Donna K Arnett and Joshua C Bis and John Blangero and Eric Boerwinkle and Donald W Bowden and Brian E Cade and Jenna C Carlson and April P Carson and Yii-Der Ida Chen and Joanne E Curran and Paul S de Vries and Susan K Dutcher and Patrick T Ellinor and James S Floyd and Myriam Fornage and Barry I Freedman and Stacey Gabriel and Soren Germer and Richard A Gibbs and Xiuqing Guo and Jiang He and Nancy Heard-Costa and Bertha Hildalgo and Lifang Hou and Marguerite R Irvin and Roby Joehanes and Robert C Kaplan and Sharon Lr Kardia and Tanika N Kelly and Ryan Kim and Charles Kooperberg and Brian G Kral and Daniel Levy and Changwei Li and Chunyu Liu and Don Lloyd-Jone and Ruth Jf Loos and Michael C Mahaney and Lisa W Martin and Rasika A Mathias and Ryan L Minster and Braxton D Mitchell and May E Montasser and Alanna C Morrison and Joanne M Murabito and Take Naseri and Jeffrey R O'Connell and Nicholette D Palmer and Michael H Preuss and Bruce M Psaty and Laura M Raffield and Dabeeru C Rao and Susan Redline and Alexander P Reiner and Stephen S Rich and Muagututi'a Sefuiva Ruepena and Wayne H-H Sheu and Jennifer A Smith and Albert Smith and Hemant K Tiwari and Michael Y Tsai and Karine A Viaud-Martinez and Zhe Wang and Lisa R Yanek and Wei Zhao and  and Jerome I Rotter and Xihong Lin and Pradeep Natarajan and Gina M Peloso},
doi = {10.1101/2023.06.28.23291966},
year  = {2023},
date = {2023-06-01},
journal = {medRxiv},
abstract = {Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37425786,
title = {Integrative metabolomics differentiate coronary artery disease, peripheral artery disease, and venous thromboembolism risks},
author = {Jiwoo Lee and Thomas Gilliland and Satoshi Koyama and Tetsushi Nakao and Jacqueline Dron and Kim Lannery and Megan Wong and Gina M Peloso and Whitney Hornsby and Pradeep Natarajan},
doi = {10.1101/2023.06.21.23291103},
year  = {2023},
date = {2023-06-01},
journal = {medRxiv},
abstract = {RATIONALE: Arterial and venous cardiovascular conditions, such as coronary artery disease (CAD), peripheral artery disease (PAD), and venous thromboembolism (VTE), are genetically correlated. Interrogating distinct and overlapping mechanisms may shed new light on disease mechanisms.nnOBJECTIVE: In this study, we aimed to: identify and compare (1) epidemiologic and (2) causal, genetic relationships between metabolites and CAD, PAD, and VTE.nnMETHODS: We used metabolomic data from 95,402 individuals in the UK Biobank, excluding individuals with prevalent cardiovascular disease. Logistic regression models adjusted for age, sex, genotyping array, first five principal components of ancestry, and statin use estimated the epidemiologic associations of 249 metabolites with incident CAD, PAD, or VTE. Bidirectional two-sample Mendelian randomization (MR) estimated the causal effects between metabolites and cardiovascular phenotypes using genome-wide association summary statistics for metabolites (N = 118,466 from UK Biobank), CAD (N = 184,305 from CARDIoGRAMplusC4D 2015), PAD (N = 243,060 from Million Veterans Project) and VTE (N = 650,119 from Million Veterans Project). Multivariable MR (MVMR) was performed in subsequent analyses.nnRESULTS: We found that 194, 111, and 69 metabolites were epidemiologically associated (P < 0.001) with CAD, PAD, and VTE, respectively. Metabolomic profiles exhibited variable similarity between disease pairs: CAD and PAD (N = 100 shared associations, R  = 0.499), CAD and VTE (N = 68, R  = 0.455), and PAD and VTE (N = 54, R  = 0.752). MR revealed 28 metabolites that increased risk for both CAD and PAD and 2 metabolites that increased risk for CAD but decreased risk for VTE. Despite strong epidemiologic overlap, no metabolites had a shared genetic relationship between PAD and VTE. MVMR revealed several metabolites with shared causal effects on CAD and PAD related to cholesterol content within very-low-density lipoprotein particles.nnCONCLUSIONS: While common arterial and venous conditions are associated with overlapping metabolomic profiles, MR prioritized the role of remnant cholesterol in arterial diseases but not venous thrombosis.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37426450,
title = {Minimum information and guidelines for reporting a Multiplexed Assay of Variant Effect},
author = {Melina Claussnitzer and Victoria N Parikh and Alex H Wagner and Jeremy A Arbesfeld and Carol J Bult and Helen V Firth and Lara A Muffley and Alex N Nguyen Ba and Kevin Riehle and Frederick P Roth and Daniel Tabet and Benedetta Bolognesi and Andrew M Glazer and Alan F Rubin},
issn = {2331-8422},
year  = {2023},
date = {2023-06-01},
journal = {ArXiv},
abstract = {Multiplexed Assays of Variant Effect (MAVEs) have emerged as a powerful approach for interrogating thousands of genetic variants in a single experiment. The flexibility and widespread adoption of these techniques across diverse disciplines has led to a heterogeneous mix of data formats and descriptions, which complicates the downstream use of the resulting datasets. To address these issues and promote reproducibility and reuse of MAVE data, we define a set of minimum information standards for MAVE data and metadata and outline a controlled vocabulary aligned with established biomedical ontologies for describing these experimental designs.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37253541,
title = {Discordant calls across genotype discovery approaches elucidate variants with systematic errors},
author = {Elizabeth G Atkinson and Mykyta Artomov and Alexander A Loboda and Heidi L Rehm and Daniel G MacArthur and Konrad J Karczewski and Benjamin M Neale and Mark J Daly},
doi = {10.1101/gr.277908.123},
issn = {1549-5469},
year  = {2023},
date = {2023-06-01},
journal = {Genome Res},
volume = {33},
number = {6},
pages = {999--1005},
abstract = {Large-scale high-throughput sequencing data sets have been transformative for informing clinical variant interpretation and for use as reference panels for statistical and population genetic efforts. Although such resources are often treated as ground truth, we find that in widely used reference data sets such as the Genome Aggregation Database (gnomAD), some variants pass gold-standard filters, yet are systematically different in their genotype calls across genotype discovery approaches. The inclusion of such discordant sites in study designs involving multiple genotype discovery strategies could bias results and lead to false-positive hits in association studies owing to technological artifacts rather than a true relationship to the phenotype. Here, we describe this phenomenon of discordant genotype calls across genotype discovery approaches, characterize the error mode of wrong calls, provide a list of discordant sites identified in gnomAD that should be treated with caution in analyses, and present a metric and machine learning classifier trained on gnomAD data to identify likely discordant variants in other data sets. We find that different genotype discovery approaches have different sets of variants at which this problem occurs, but there are characteristic variant features that can be used to predict discordant behavior. Discordant sites are largely shared across ancestry groups, although different populations are powered for the discovery of different variants. We find that the most common error mode is that of a variant being heterozygous for one approach and homozygous for the other, with heterozygous in the genomes and homozygous reference in the exomes making up the majority of miscalls.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37315093,
title = {Major Genetic Risk Factors for Dupuytren's Disease Are Inherited From Neandertals},
author = {Richard Ågren and Snehal Patil and Xiang Zhou and  and Kristoffer Sahlholm and Svante Pääbo and Hugo Zeberg},
doi = {10.1093/molbev/msad130},
issn = {1537-1719},
year  = {2023},
date = {2023-06-01},
journal = {Mol Biol Evol},
volume = {40},
number = {6},
abstract = {Dupuytren's disease is characterized by fingers becoming permanently bent in a flexed position. Whereas people of African ancestry are rarely afflicted by Dupuytren's disease, up to ∼30% of men over 60 years suffer from this condition in northern Europe. Here, we meta-analyze 3 biobanks comprising 7,871 cases and 645,880 controls and find 61 genome-wide significant variants associated with Dupuytren's disease. We show that 3 of the 61 loci harbor alleles of Neandertal origin, including the second and third most strongly associated ones (P = 6.4 × 10-132 and P = 9.2 × 10-69, respectively). For the most strongly associated Neandertal variant, we identify EPDR1 as the causal gene. Dupuytren's disease is an example of how admixture with Neandertals has shaped regional differences in disease prevalence.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37425834,
title = {CHARR efficiently estimates contamination from DNA sequencing data},
author = {Wenhan Lu and Laura D Gauthier and Timothy Poterba and Edoardo Giacopuzzi and Julia K Goodrich and Christine R Stevens and Daniel King and Mark J Daly and Benjamin M Neale and Konrad J Karczewski},
doi = {10.1101/2023.06.28.545801},
year  = {2023},
date = {2023-06-01},
journal = {bioRxiv},
abstract = {DNA sample contamination is a major issue in clinical and research applications of whole genome and exome sequencing. Even modest levels of contamination can substantially affect the overall quality of variant calls and lead to widespread genotyping errors. Currently, popular tools for estimating the contamination level use short-read data (BAM/CRAM files), which are expensive to store and manipulate and often not retained or shared widely. We propose a new metric to estimate DNA sample contamination from variant-level whole genome and exome sequence data, CHARR, Contamination from Homozygous Alternate Reference Reads, which leverages the infiltration of reference reads within homozygous alternate variant calls. CHARR uses a small proportion of variant-level genotype information and thus can be computed from single-sample gVCFs or callsets in VCF or BCF formats, as well as efficiently stored variant calls in Hail VDS format. Our results demonstrate that CHARR accurately recapitulates results from existing tools with substantially reduced costs, improving the accuracy and efficiency of downstream analyses of ultra-large whole genome and exome sequencing datasets.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37202553,
title = {Genetic patterning for child psychopathology is distinct from that for adults and implicates fetal cerebellar development},
author = {Dylan E Hughes and Keiko Kunitoki and Safia Elyounssi and Mannan Luo and Oren M Bazer and Casey E Hopkinson and Kevin F Dowling and Alysa E Doyle and Erin C Dunn and Hamdi Eryilmaz and Jodi M Gilman and Daphne J Holt and Eve M Valera and Jordan W Smoller and Charlotte A M Cecil and Henning Tiemeier and Phil H Lee and Joshua L Roffman},
doi = {10.1038/s41593-023-01321-8},
issn = {1546-1726},
year  = {2023},
date = {2023-06-01},
journal = {Nat Neurosci},
volume = {26},
number = {6},
pages = {959--969},
abstract = {Childhood psychiatric symptoms are often diffuse but can coalesce into discrete mental illnesses during late adolescence. We leveraged polygenic scores (PGSs) to parse genomic risk for childhood symptoms and to uncover related neurodevelopmental mechanisms with transcriptomic and neuroimaging data. In independent samples (Adolescent Brain Cognitive Development, Generation R) a narrow cross-disorder neurodevelopmental PGS, reflecting risk for attention deficit hyperactivity disorder, autism, depression and Tourette syndrome, predicted psychiatric symptoms through early adolescence with greater sensitivity than broad cross-disorder PGSs reflecting shared risk across eight psychiatric disorders, the disorder-specific PGS individually or two other narrow cross-disorder (Compulsive, Mood-Psychotic) scores. Neurodevelopmental PGS-associated genes were preferentially expressed in the cerebellum, where their expression peaked prenatally. Further, lower gray matter volumes in cerebellum and functionally coupled cortical regions associated with psychiatric symptoms in mid-childhood. These findings demonstrate that the genetic underpinnings of pediatric psychiatric symptoms differ from those of adult illness, and implicate fetal cerebellar developmental processes that endure through childhood.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37327038,
title = {Mobile Apps for Dietary and Food Timing Assessment: Evaluation for Use in Clinical Research},
author = {Siena Gioia and Irma M Vlasac and Demsina Babazadeh and Noah L Fryou and Elizabeth Do and Jessica Love and Rebecca Robbins and Hassan S Dashti and Jacqueline M Lane},
doi = {10.2196/35858},
issn = {2561-326X},
year  = {2023},
date = {2023-06-01},
journal = {JMIR Form Res},
volume = {7},
pages = {e35858},
abstract = {BACKGROUND: Over the last decade, health mobile apps have become an increasingly popular tool used by clinicians and researchers to track food consumption and exercise. However, many consumer apps lack the technological features for facilitating the capture of critical food timing details.nnOBJECTIVE: This study aimed to introduce users to 11 apps from US app stores that recorded both dietary intake and food timing to establish which one would be the most appropriate for clinical research.nnMETHODS: To determine a viable app that recorded both dietary intake and food timing for use in a food timing-related clinical study, we evaluated the time stamp data, usability, privacy policies, the accuracy of nutrient estimates, and general features of 11 mobile apps for dietary assessment that were available on US app stores. The following apps were selected using a keyword search of related terms and reviewed: text entry apps-Cronometer, DiaryNutrition, DietDiary, FoodDiary, Macros, and MyPlate; image entry apps-FoodView and MealLogger; and text plus image entry apps-Bitesnap, myCircadianClock, and MyFitnessPal.nnRESULTS: Our primary goal was to identify apps that recorded food time stamps, which 8 (73%) of the 11 reviewed apps did. Of the 11 apps, only 4 (36%) allowed users to edit the time stamps. Next, we sought to evaluate the usability of the apps using the System Usability Scale across 2 days, and 82% (9/11) of the apps received favorable scores for usability. To enable use in research and clinical settings, the privacy policies of each app were systematically reviewed using common criteria, with 1 (9%) Health Insurance Portability and Accountability Act-compliant app (Cronometer). Furthermore, protected health information was collected by 9 (82%) of the 11 apps. Finally, to assess the accuracy of the nutrient estimates generated by these apps, we selected 4 sample food items and a 3-day dietary record to input into each app. The caloric and macronutrient estimates of the apps were compared with the nutrient estimates provided by a registered dietitian using the Nutrition Data System for Research database. In terms of the 3-day food record, the apps were found to consistently underestimate daily calories and macronutrients compared with the Nutrition Data System for Research output.nnCONCLUSIONS: Overall, we found that the Bitesnap app provided flexible dietary and food timing functionality capable of being used in research and clinical settings, whereas most other apps lacked in the necessary food timing functionality or user privacy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36799620,
title = {Design and Implementation of the All of Us Research Program COVID-19 Participant Experience (COPE) Survey},
author = {Claire E Schulkey and Tamara R Litwin and Genevieve Ellsworth and Heather Sansbury and Brian K Ahmedani and Karmel W Choi and Robert M Cronin and Yasmin Kloth and Alan W Ashbeck and Scott Sutherland and Brandy M Mapes and Mark Begale and Geeta Bhat and Paula King and Kayla Marginean and Keri Ann Wolfe and Aymone Kouame and Carmina Raquel and Francis Ratsimbazafy and Zach Bornemeier and Kyle Neumeier and Rubin Baskir and Kelly A Gebo and Joshua Denny and Jordan W Smoller and Holly A Garriock},
doi = {10.1093/aje/kwad035},
issn = {1476-6256},
year  = {2023},
date = {2023-06-01},
journal = {Am J Epidemiol},
volume = {192},
number = {6},
pages = {972--986},
abstract = {In response to the rapidly evolving coronavirus disease 2019 (COVID-19) pandemic, the All of Us Research Program longitudinal cohort study developed the COVID-19 Participant Experience (COPE) survey to better understand the pandemic experiences and health impacts of COVID-19 on diverse populations within the United States. Six survey versions were deployed between May 2020 and March 2021, covering mental health, loneliness, activity, substance use, and discrimination, as well as COVID-19 symptoms, testing, treatment, and vaccination. A total of 104,910 All of Us Research Program participants, of whom over 73% were from communities traditionally underrepresented in biomedical research, completed 275,201 surveys; 9,693 completed all 6 surveys. Response rates varied widely among demographic groups and were lower among participants from certain racial and ethnic minority populations, participants with low income or educational attainment, and participants with a Spanish language preference. Survey modifications improved participant response rates between the first and last surveys (13.9% to 16.1%, P < 0.001). This paper describes a data set with longitudinal COVID-19 survey data in a large, diverse population that will enable researchers to address important questions related to the pandemic, a data set that is of additional scientific value when combined with the program's other data sources.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37333223,
title = {Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease},
author = {Hyun-Sik Yang and Ling Teng and Daniel Kang and Vilas Menon and Tian Ge and Hilary K Finucane and Aaron P Schultz and Michael Properzi and Hans-Ulrich Klein and Lori B Chibnik and Julie A Schneider and David A Bennett and Timothy J Hohman and Richard P Mayeux and Keith A Johnson and Philip L De Jager and Reisa A Sperling},
doi = {10.1101/2023.06.01.23290850},
year  = {2023},
date = {2023-06-01},
journal = {medRxiv},
abstract = {Alzheimer's disease (AD) heritability is enriched in glial genes, but how and when cell-type-specific genetic risk contributes to AD remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets. In an autopsy dataset spanning all stages of AD (n=1,457), astrocytic (Ast) ADPRS was associated with both diffuse and neuritic Aβ plaques, while microglial (Mic) ADPRS was associated with neuritic Aβ plaques, microglial activation, tau, and cognitive decline. Causal modeling analyses further clarified these relationships. In an independent neuroimaging dataset of cognitively unimpaired elderly (n=2,921), Ast-ADPRS were associated with Aβ, and Mic-ADPRS was associated with Aβ and tau, showing a consistent pattern with the autopsy dataset. Oligodendrocytic and excitatory neuronal ADPRSs were associated with tau, but only in the autopsy dataset including symptomatic AD cases. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37280210,
title = {Chromatin alternates between A and B compartments at kilobase scale for subgenic organization},
author = {Hannah L Harris and Huiya Gu and Moshe Olshansky and Ailun Wang and Irene Farabella and Yossi Eliaz and Achyuth Kalluchi and Akshay Krishna and Mozes Jacobs and Gesine Cauer and Melanie Pham and Suhas S P Rao and Olga Dudchenko and Arina Omer and Kiana Mohajeri and Sungjae Kim and Michael H Nichols and Eric S Davis and Dimos Gkountaroulis and Devika Udupa and Aviva Presser Aiden and Victor G Corces and Douglas H Phanstiel and William Stafford Noble and Guy Nir and Michele Di Pierro and Jeong-Sun Seo and Michael E Talkowski and Erez Lieberman Aiden and M Jordan Rowley},
doi = {10.1038/s41467-023-38429-1},
issn = {2041-1723},
year  = {2023},
date = {2023-06-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {3303},
abstract = {Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal interactions remains enigmatic. Here, we critically examine nuclear compartments and CTCF loop-proximal interactions using a combination of in situ Hi-C at unparalleled depth, algorithm development, and biophysical modeling. Producing a large Hi-C map with 33 billion contacts in conjunction with an algorithm for performing principal component analysis on sparse, super massive matrices (POSSUMM), we resolve compartments to 500 bp. Our results demonstrate that essentially all active promoters and distal enhancers localize in the A compartment, even when flanking sequences do not. Furthermore, we find that the TSS and TTS of paused genes are often segregated into separate compartments. We then identify diffuse interactions that radiate from CTCF loop anchors, which correlate with strong enhancer-promoter interactions and proximal transcription. We also find that these diffuse interactions depend on CTCF's RNA binding domains. In this work, we demonstrate features of fine-scale chromatin organization consistent with a revised model in which compartments are more precise than commonly thought while CTCF loops are more protracted.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37104866,
title = {The Rare and Atypical Diabetes Network (RADIANT) Study: Design and Early Results},
author = { },
doi = {10.2337/dc22-2440},
issn = {1935-5548},
year  = {2023},
date = {2023-06-01},
journal = {Diabetes Care},
volume = {46},
number = {6},
pages = {1265--1270},
abstract = {OBJECTIVE: The Rare and Atypical Diabetes Network (RADIANT) will perform a study of individuals and, if deemed informative, a study of their family members with uncharacterized forms of diabetes.nnRESEARCH DESIGN AND METHODS: The protocol includes genomic (whole-genome [WGS], RNA, and mitochondrial sequencing), phenotypic (vital signs, biometric measurements, questionnaires, and photography), metabolomics, and metabolic assessments.nnRESULTS: Among 122 with WGS results of 878 enrolled individuals, a likely pathogenic variant in a known diabetes monogenic gene was found in 3 (2.5%), and six new monogenic variants have been identified in the SMAD5, PTPMT1, INS, NFKB1, IGF1R, and PAX6 genes. Frequent phenotypic clusters are lean type 2 diabetes, autoantibody-negative and insulin-deficient diabetes, lipodystrophic diabetes, and new forms of possible monogenic or oligogenic diabetes.nnCONCLUSIONS: The analyses will lead to improved means of atypical diabetes identification. Genetic sequencing can identify new variants, and metabolomics and transcriptomics analysis can identify novel mechanisms and biomarkers for atypical disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37333246,
title = {Selection, optimization, and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse populations},
author = {Niall J Lennon and Leah C Kottyan and Christopher Kachulis and Noura Abul-Husn and Josh Arias and Gillian Belbin and Jennifer E Below and Sonja Berndt and Wendy Chung and James J Cimino and Ellen Wright Clayton and John J Connolly and David Crosslin and Ozan Dikilitas and Digna R Velez Edwards and QiPing Feng and Marissa Fisher and Robert Freimuth and Tian Ge and  and  and Joseph T Glessner and Adam Gordon and Candace Guiducci and Hakon Hakonarson and Maegan Harden and Margaret Harr and Joel Hirschhorn and Clive Hoggart and Li Hsu and Ryan Irvin and Gail P Jarvik and Elizabeth W Karlson and Atlas Khan and Amit Khera and Krzysztof Kiryluk and Iftikhar Kullo and Katie Larkin and Nita Limdi and Jodell E Linder and Ruth Loos and Yuan Luo and Edyta Malolepsza and Teri Manolio and Lisa J Martin and Li McCarthy and James B Meigs and Tesfaye B Mersha and Jonathan Mosley and Bahram Namjou and Nihal Pai and Lorenzo L Pesce and Ulrike Peters and Josh Peterson and Cynthia A Prows and Megan J Puckelwartz and Heidi Rehm and Dan Roden and Elisabeth A Rosenthal and Robb Rowley and Konrad Teodor Sawicki and Dan Schaid and Tara Schmidlen and Roelof Smit and Johanna Smith and Jordan W Smoller and Minta Thomas and Hemant Tiwari and Diana Toledo and Nataraja Sarma Vaitinadin and David Veenstra and Theresa Walunas and Zhe Wang and Wei-Qi Wei and Chunhua Weng and Georgia Wiesner and Yin Xianyong and Eimear Kenny},
doi = {10.1101/2023.05.25.23290535},
year  = {2023},
date = {2023-06-01},
journal = {medRxiv},
abstract = {Polygenic risk scores (PRS) have improved in predictive performance supporting their use in clinical practice. Reduced predictive performance of PRS in diverse populations can exacerbate existing health disparities. The NHGRI-funded eMERGE Network is returning a PRS-based genome-informed risk assessment to 25,000 diverse adults and children. We assessed PRS performance, medical actionability, and potential clinical utility for 23 conditions. Standardized metrics were considered in the selection process with additional consideration given to strength of evidence in African and Hispanic populations. Ten conditions were selected with a range of high-risk thresholds: atrial fibrillation, breast cancer, chronic kidney disease, coronary heart disease, hypercholesterolemia, prostate cancer, asthma, type 1 diabetes, obesity, and type 2 diabetes. We developed a pipeline for clinical PRS implementation, used genetic ancestry to calibrate PRS mean and variance, created a framework for regulatory compliance, and developed a PRS clinical report. eMERGE's experience informs the infrastructure needed to implement PRS-based implementation in diverse clinical settings.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37347618,
title = {Portable MRI to assess optic chiasm decompression after endoscopic endonasal resection of sellar and suprasellar lesions},
author = {Christopher S Hong and Layton A Lamsam and Vineetha Yadlapalli and Nethra Parasuram and Mercy Mazurek and Isha Chavva and Dheeraj Lalwani and Julia Zabinska and Steven J Schiff and R Peter Manes and Eugenia M Vining and Ryan A Rimmer and W Taylor Kimberly and Kevin N Sheth and Sacit Bulent Omay},
doi = {10.3171/2023.5.JNS23174},
issn = {1933-0693},
year  = {2023},
date = {2023-06-01},
journal = {J Neurosurg},
pages = {1--7},
abstract = {OBJECTIVE: Low-field portable MRI (pMRI) is a recent technological advancement with potential for broad applications. Compared with conventional MRI, pMRI is less resource-intensive with regard to operational costs and scan time. The application of pMRI in neurosurgical oncology has not been previously described. The goal of this study was to demonstrate the efficacy of pMRI in assessing optic nerve decompression after endoscopic endonasal surgery for sellar and suprasellar pathologies.nnMETHODS: Patients who underwent endoscopic endonasal surgery for sellar and suprasellar lesions at a single institution and for whom pMRI and routine MRI were performed postoperatively were retrospectively reviewed to compare the two imaging systems. To assess the relative resolution of pMRI compared with MRI, the distance from the optic chiasm to the top of the third ventricle was measured, and the measurements were compared between paired equivalent slices on T2-weighted coronal images. The inter- and intrarater correlations were analyzed.nnRESULTS: Twelve patients were included in this study (10 with pituitary adenomas and 2 with craniopharyngiomas) with varying degrees of optic chiasm compression on preoperative imaging. Measurements were averaged across raters before calculating agreement between pMRI and MRI, which demonstrated significant interrater reliability (intraclass correlation coefficient [ICC] = 0.78, p < 0.01). Agreement between raters within the pMRI measurements was also significantly reliable (ICC = 0.93, p < 0.01). Finally, a linear mixed-effects model was specified to demonstrate that MRI measurement could be predicted using the pMRI measurement with the patient and rater set as random effects (pMRI β coefficient = 0.80, p < 0.01).nnCONCLUSIONS: The results of this study suggest that resolution of pMRI is comparable to that of conventional MRI in assessing the optic chiasm position in relation to the third ventricle. Portable MRI sufficiently demonstrates decompression of the optic chiasm after endoscopic endonasal surgery. It can be an alternative strategy in cases in which cost, scan-time considerations, or lack of intraoperative MRI availability may preclude the ability to assess adequate optic nerve decompression after endoscopic endonasal surgery for sellar and suprasellar lesions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37330696,
title = {Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting},
author = {Kimberly K Diaz Perez and Sarah W Curtis and Alba Sanchis-Juan and Xuefang Zhao and Taylor Head and Samantha Ho and Bridget Carter and Toby McHenry and Madison R Bishop and Luz C Valencia-Ramirez and Claudia Restrepo and Jacqueline T Hecht and Lina M Uribe and George Wehby and Seth M Weinberg and Terri H Beaty and Jeffrey C Murray and Eleanor Feingold and Mary L Marazita and David J Cutler and Michael P Epstein and Harrison Brand and Elizabeth J Leslie},
doi = {10.1016/j.gim.2023.100918},
issn = {1530-0366},
year  = {2023},
date = {2023-06-01},
journal = {Genet Med},
volume = {25},
number = {10},
pages = {100918},
abstract = {PURPOSE: Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls.nnMETHODS: We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria.nnRESULTS: 9.04% of cases and 1.02% of controls had "likely pathogenic" variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were "variants of uncertain significance", occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance.nnCONCLUSION: These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37291194,
title = {Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake},
author = {Alice Williamson and Dougall M Norris and Xianyong Yin and K Alaine Broadaway and Anne H Moxley and Swarooparani Vadlamudi and Emma P Wilson and Anne U Jackson and Vasudha Ahuja and Mette K Andersen and Zorayr Arzumanyan and Lori L Bonnycastle and Stefan R Bornstein and Maxi P Bretschneider and Thomas A Buchanan and Yi-Cheng Chang and Lee-Ming Chuang and Ren-Hua Chung and Tine D Clausen and Peter Damm and Graciela E Delgado and Vanessa D de Mello and Josée Dupuis and Om P Dwivedi and Michael R Erdos and Lilian Fernandes Silva and Timothy M Frayling and Christian Gieger and Mark O Goodarzi and Xiuqing Guo and Stefan Gustafsson and Liisa Hakaste and Ulf Hammar and Gad Hatem and Sandra Herrmann and Kurt Højlund and Katrin Horn and Willa A Hsueh and Yi-Jen Hung and Chii-Min Hwu and Anna Jonsson and Line L Kårhus and Marcus E Kleber and Peter Kovacs and Timo A Lakka and Marie Lauzon and I-Te Lee and Cecilia M Lindgren and Jaana Lindström and Allan Linneberg and Ching-Ti Liu and Jian'an Luan and Dina Mansour Aly and Elisabeth Mathiesen and Angela P Moissl and Andrew P Morris and Narisu Narisu and Nikolaos Perakakis and Annette Peters and Rashmi B Prasad and Roman N Rodionov and Kathryn Roll and Carsten F Rundsten and Chloé Sarnowski and Kai Savonen and Markus Scholz and Sapna Sharma and Sara E Stinson and Sufyan Suleman and Jingyi Tan and Kent D Taylor and Matti Uusitupa and Dorte Vistisen and Daniel R Witte and Romy Walther and Peitao Wu and Anny H Xiang and Björn Zethelius and  and Emma Ahlqvist and Richard N Bergman and Yii-Der Ida Chen and Francis S Collins and Tove Fall and Jose C Florez and Andreas Fritsche and Harald Grallert and Leif Groop and Torben Hansen and Heikki A Koistinen and Pirjo Komulainen and Markku Laakso and Lars Lind and Markus Loeffler and Winfried März and James B Meigs and Leslie J Raffel and Rainer Rauramaa and Jerome I Rotter and Peter E H Schwarz and Michael Stumvoll and Johan Sundström and Anke Tönjes and Tiinamaija Tuomi and Jaakko Tuomilehto and Robert Wagner and Inês Barroso and Mark Walker and Niels Grarup and Michael Boehnke and Nicholas J Wareham and Karen L Mohlke and Eleanor Wheeler and Stephen O'Rahilly and Daniel J Fazakerley and Claudia Langenberg},
doi = {10.1038/s41588-023-01408-9},
issn = {1546-1718},
year  = {2023},
date = {2023-06-01},
journal = {Nat Genet},
volume = {55},
number = {6},
pages = {973--983},
abstract = {Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37144470,
title = {Sound and light levels in intensive care units in a large urban hospital in the United States},
author = {Michael J Leone and Hassan S Dashti and Brian Coughlin and Ryan A Tesh and Syed A Quadri and Abigail A Bucklin and Noor Adra and Parimala Velpula Krishnamurthy and Elissa M Ye and Aashritha Hemmige and Subapriya Rajan and Ezhil Panneerselvam and Jasmine Higgins and Muhammad Abubakar Ayub and Wolfgang Ganglberger and Luis Paixao and Timothy T Houle and B Taylor Thompson and Oluwaseun Johnson-Akeju and Richa Saxena and Eyal Kimchi and Sydney S Cash and Robert J Thomas and M Brandon Westover},
doi = {10.1080/07420528.2023.2207647},
issn = {1525-6073},
year  = {2023},
date = {2023-06-01},
journal = {Chronobiol Int},
volume = {40},
number = {6},
pages = {759--768},
abstract = {Intensive care units (ICUs) may disrupt sleep. Quantitative ICU studies of concurrent and continuous sound and light levels and timings remain sparse in part due to the lack of ICU equipment that monitors sound and light. Here, we describe sound and light levels across three adult ICUs in a large urban United States tertiary care hospital using a novel sensor. The novel sound and light sensor is composed of a Gravity Sound Level Meter for sound level measurements and an Adafruit TSL2561 digital luminosity sensor for light levels. Sound and light levels were continuously monitored in the room of 136 patients (mean age = 67.0 (8.7) years, 44.9% female) enrolled in the Investigation of Sleep in the Intensive Care Unit study (ICU-SLEEP; Clinicaltrials.gov: #NCT03355053), at the Massachusetts General Hospital. The hours of available sound and light data ranged from 24.0 to 72.2 hours. Average sound and light levels oscillated throughout the day and night. On average, the loudest hour was 17:00 and the quietest hour was 02:00. Average light levels were brightest at 09:00 and dimmest at 04:00. For all participants, average nightly sound levels exceeded the WHO guideline of < 35 decibels. Similarly, mean nightly light levels varied across participants (minimum: 1.00 lux, maximum: 577.05 lux). Sound and light events were more frequent between 08:00 and 20:00 than between 20:00 and 08:00 and were largely similar on weekdays and weekend days. Peaks in distinct alarm frequencies (Alarm 1) occurred at 01:00, 06:00, and at 20:00. Alarms at other frequencies (Alarm 2) were relatively consistent throughout the day and night, with a small peak at 20:00. In conclusion, we present a sound and light data collection method and results from a cohort of critically ill patients, demonstrating excess sound and light levels across multiple ICUs in a large tertiary care hospital in the United States. ClinicalTrials.gov, #NCT03355053. Registered 28 November 2017, https://clinicaltrials.gov/ct2/show/NCT03355053.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37333361,
title = {Association of Clonal Hematopoiesis of Indeterminate Potential with Incident Heart Failure with Preserved Ejection Fraction},
author = {Alex P Reiner and Mary B Roberts and Michael C Honigberg and Charles Kooperberg and Pinkal Desai and Alexander G Bick and Pradeep Natarajan and JoAnn E Manson and Eric A Whitsel and Charles B Eaton},
doi = {10.1101/2023.06.07.23291038},
year  = {2023},
date = {2023-06-01},
journal = {medRxiv},
abstract = {BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) was recently identified as a risk factor for incident heart failure (HF). Whether CHIP is associated selectively with risk of heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) subtypes is unknown.nnOBJECTIVES: To evaluate whether CHIP is associated with incident HF subtypes, HFrEF versus HFpEF.nnMETHODS: We obtained CHIP status from whole genome sequencing of blood DNA in participants without prevalent HF from a multi-ethnic sample of post-menopausal women without prevalent HF (N=5,214) from the Women's Health Initiative (WHI). Cox proportional hazards models were performed, adjusting for demographic and clinical risk factors.nnRESULTS: CHIP was significantly associated with a 42% (95%CI 6%, 91%) increased risk of HFpEF (P=0.02). In contrast, there was no evidence of association between CHIP and risk of incident HFrEF. When the three most common CHIP subtypes were assessed individually, the risk of HFpEF was more strongly associated with TET2 (HR=2.5; 95%CI 1.54, 4.06; P<0.001), than DNMT3A or ASXL1.nnCONCLUSION: CHIP, particularly mutations in  , represents a potential new risk factor for incident HFpEF.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36578216,
title = {Computed Tomography Lesions and Their Association With Global Outcome in Young People With Mild Traumatic Brain Injury},
author = {Lennart Riemann and Ana Mikolic and Andrew Maas and Andreas Unterberg and Alexander Younsi and },
doi = {10.1089/neu.2022.0055},
issn = {1557-9042},
year  = {2023},
date = {2023-06-01},
journal = {J Neurotrauma},
volume = {40},
number = {11-12},
pages = {1243--1254},
abstract = {Mild traumatic brain injury (mTBI) can be accompanied by structural damage to the brain. Here, we investigated how the presence of intracranial traumatic computed tomography (CT) pathologies relates to the global functional outcome in young patients one year after mTBI. All patients with mTBI (Glasgow Coma Scale: 13-15) ≤24 years in the multi-center, prospective, observational Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study were included. Patient demographics and CT findings were assessed at admission, and the Glasgow Outcome Scale Extended (GOSE) was evaluated at 12 months follow-up. The association between a "positive CT" (at least one of the following: epidural hematoma, subdural hematoma, traumatic subarachnoid hemorrhage (tSAH), intraventricular hemorrhage, subdural collection mixed density, contusion, traumatic axonal injury) and functional outcome (GOSE) was assessed using multi-variable mixed ordinal and logistic regression models. A total of 462 patients with mTBI and initial brain CT from 46 study centers were included. The median age was 19 (17-22) years, and 322 (70%) were males. CT imaging showed a traumatic intracranial pathology in 171 patients (37%), most commonly tSAH (48%), contusions (40%), and epidural hematomas (37%). Patients with a positive CT scan were less likely to achieve a complete recovery 12 months post-injury. The presence of any CT abnormality was associated with both lower GOSE scores (odds ratio [OR]: 0.39 [0.24-0.63]) and incomplete recovery (GOSE <8; OR: 0.41 [0.25-0.68]), also when adjusted for demographical and clinical baseline factors. The presence of intracranial traumatic CT pathologies was predictive of outcome 12 months after mTBI in young patients, which might help to identify candidates for early follow-up and additional care.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37194416,
title = {Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome},
author = {Jonai Pujol-Giménez and Ghayda Mirzaa and Elizabeth E Blue and Giuseppe Albano and Danny E Miller and Aimee Allworth and James T Bennett and Peter H Byers and Sirisak Chanprasert and Jingheng Chen and Daniel Doherty and Andrew B Folta and Madelyn A Gillentine and Ian Glass and Anne Hing and Martha Horike-Pyne and Kathleen A Leppig and Azma Parhin and Jane Ranchalis and Wendy H Raskind and Elisabeth A Rosenthal and Ulrike Schwarze and Sam Sheppeard and Samuel Strohbehn and Virginia P Sybert and Andrew Timms and Mark Wener and  and Michael J Bamshad and Fuki M Hisama and Gail P Jarvik and Katrina M Dipple and Matthias A Hediger and Andrew B Stergachis},
doi = {10.1002/acn3.51786},
issn = {2328-9503},
year  = {2023},
date = {2023-06-01},
journal = {Ann Clin Transl Neurol},
volume = {10},
number = {6},
pages = {1046--1053},
abstract = {SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37231097,
title = {The impact of rare protein coding genetic variation on adult cognitive function},
author = {Chia-Yen Chen and Ruoyu Tian and Tian Ge and Max Lam and Gabriela Sanchez-Andrade and Tarjinder Singh and Lea Urpa and Jimmy Z Liu and Mark Sanderson and Christine Rowley and Holly Ironfield and Terry Fang and  and  and  and Mark Daly and Aarno Palotie and Ellen A Tsai and Hailiang Huang and Matthew E Hurles and Sebastian S Gerety and Todd Lencz and Heiko Runz},
doi = {10.1038/s41588-023-01398-8},
issn = {1546-1718},
year  = {2023},
date = {2023-06-01},
journal = {Nat Genet},
volume = {55},
number = {6},
pages = {927--938},
abstract = {Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37262156,
title = {The landscape of tolerated genetic variation in humans and primates},
author = {Hong Gao and Tobias Hamp and Jeffrey Ede and Joshua G Schraiber and Jeremy McRae and Moriel Singer-Berk and Yanshen Yang and Anastasia S D Dietrich and Petko P Fiziev and Lukas F K Kuderna and Laksshman Sundaram and Yibing Wu and Aashish Adhikari and Yair Field and Chen Chen and Serafim Batzoglou and Francois Aguet and Gabrielle Lemire and Rebecca Reimers and Daniel Balick and Mareike C Janiak and Martin Kuhlwilm and Joseph D Orkin and Shivakumara Manu and Alejandro Valenzuela and Juraj Bergman and Marjolaine Rousselle and Felipe Ennes Silva and Lidia Agueda and Julie Blanc and Marta Gut and Dorien de Vries and Ian Goodhead and R Alan Harris and Muthuswamy Raveendran and Axel Jensen and Idriss S Chuma and Julie E Horvath and Christina Hvilsom and David Juan and Peter Frandsen and Fabiano R de Melo and Fabrício Bertuol and Hazel Byrne and Iracilda Sampaio and Izeni Farias and João Valsecchi do Amaral and Mariluce Messias and Maria N F da Silva and Mihir Trivedi and Rogerio Rossi and Tomas Hrbek and Nicole Andriaholinirina and Clément J Rabarivola and Alphonse Zaramody and Clifford J Jolly and Jane Phillips-Conroy and Gregory Wilkerson and Christian Abee and Joe H Simmons and Eduardo Fernandez-Duque and Sree Kanthaswamy and Fekadu Shiferaw and Dongdong Wu and Long Zhou and Yong Shao and Guojie Zhang and Julius D Keyyu and Sascha Knauf and Minh D Le and Esther Lizano and Stefan Merker and Arcadi Navarro and Thomas Bataillon and Tilo Nadler and Chiea Chuen Khor and Jessica Lee and Patrick Tan and Weng Khong Lim and Andrew C Kitchener and Dietmar Zinner and Ivo Gut and Amanda Melin and Katerina Guschanski and Mikkel Heide Schierup and Robin M D Beck and Govindhaswamy Umapathy and Christian Roos and Jean P Boubli and Monkol Lek and Shamil Sunyaev and Anne O'Donnell-Luria and Heidi L Rehm and Jinbo Xu and Jeffrey Rogers and Tomas Marques-Bonet and Kyle Kai-How Farh},
doi = {10.1126/science.abn8197},
issn = {1095-9203},
year  = {2023},
date = {2023-06-01},
journal = {Science},
volume = {380},
number = {6648},
pages = {eabn8153},
abstract = {Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37388914,
title = {Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias},
author = {Karri Kaivola and Ruth Chia and Jinhui Ding and Memoona Rasheed and Masashi Fujita and Vilas Menon and Ronald L Walton and Ryan L Collins and Kimberley Billingsley and Harrison Brand and Michael Talkowski and Xuefang Zhao and Ramita Dewan and Ali Stark and Anindita Ray and Sultana Solaiman and Pilar Alvarez Jerez and Laksh Malik and Ted M Dawson and Liana S Rosenthal and Marilyn S Albert and Olga Pletnikova and Juan C Troncoso and Mario Masellis and Julia Keith and Sandra E Black and Luigi Ferrucci and Susan M Resnick and Toshiko Tanaka and  and  and  and  and Eric Topol and Ali Torkamani and Pentti Tienari and Tatiana M Foroud and Bernardino Ghetti and John E Landers and Mina Ryten and Huw R Morris and John A Hardy and Letizia Mazzini and Sandra D'Alfonso and Cristina Moglia and Andrea Calvo and Geidy E Serrano and Thomas G Beach and Tanis Ferman and Neill R Graff-Radford and Bradley F Boeve and Zbigniew K Wszolek and Dennis W Dickson and Adriano Chiò and David A Bennett and Philip L De Jager and Owen A Ross and Clifton L Dalgard and J Raphael Gibbs and Bryan J Traynor and Sonja W Scholz},
doi = {10.1016/j.xgen.2023.100316},
issn = {2666-979X},
year  = {2023},
date = {2023-06-01},
journal = {Cell Genom},
volume = {3},
number = {6},
pages = {100316},
abstract = {We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in  as a novel risk locus for LBD and detected the known structural variants at the  and  loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37316189,
title = {Dominant negative variants in  cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay},
author = {Arezoo Mohajeri and Maryam Vaseghi-Shanjani and Jill A Rosenfeld and Gui Xiang Yang and Henry Lu and Mehul Sharma and Susan Lin and Areesha Salman and Meriam Waqas and Mahshid Sababi Azamian and Kim C Worley and Kate L Del Bel and Frederick K Kozak and Ronak Rahmanian and Catherine M Biggs and Kyla J Hildebrand and Seema R Lalani and Sarah K Nicholas and Daryl A Scott and Sara Mostafavi and Clara van Karnebeek and Erika Henkelman and Jessica Halparin and Connie L Yang and Linlea Armstrong and  and  and Stuart E Turvey and Anna Lehman},
doi = {10.1136/jmg-2022-109127},
issn = {1468-6244},
year  = {2023},
date = {2023-06-01},
journal = {J Med Genet},
abstract = {BACKGROUND: Helios (encoded by ), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4 regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans.nnMETHODS: We performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities.nnRESULTS: Genome sequencing revealed  heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function-repressing  transcription activity-in a dominant negative manner.nnCONCLUSION: This study is the first to describe dominant negative  variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37013900,
title = {De novo variants in MRTFB have gain-of-function activity in Drosophila and are associated with a novel neurodevelopmental phenotype with dysmorphic features},
author = {Jonathan C Andrews and Jung-Wan Mok and Oguz Kanca and Sharayu Jangam and Cynthia Tifft and Ellen F Macnamara and Bianca E Russell and Lee-Kai Wang and  and Stanley F Nelson and Hugo J Bellen and Shinya Yamamoto and May Christine V Malicdan and Michael F Wangler},
doi = {10.1016/j.gim.2023.100833},
issn = {1530-0366},
year  = {2023},
date = {2023-06-01},
journal = {Genet Med},
volume = {25},
number = {6},
pages = {100833},
abstract = {PURPOSE: Myocardin-related transcription factor B (MRTFB) is an important transcriptional regulator, which promotes the activity of an estimated 300 genes but is not known to underlie a Mendelian disorder.nnMETHODS: Probands were identified through the efforts of the Undiagnosed Disease Network. Because the MRTFB protein is highly conserved between vertebrate and invertebrate model organisms, we generated a humanized Drosophila model expressing the human MRTFB protein in the same spatial and temporal pattern as the fly gene. Actin binding assays were used to validate the effect of the variants on MRTFB.nnRESULTS: Here, we report 2 pediatric probands with de novo variants in MRTFB (p.R104G and p.A91P) and mild dysmorphic features, intellectual disability, global developmental delays, speech apraxia, and impulse control issues. Expression of the variants within wing tissues of a fruit fly model resulted in changes in wing morphology. The MRTFB and MRTFB variants also display a decreased level of actin binding within critical RPEL domains, resulting in increased transcriptional activity and changes in the organization of the actin cytoskeleton.nnCONCLUSION: The MRTFB and MRTFB variants affect the regulation of the protein and underlie a novel neurodevelopmental disorder. Overall, our data suggest that these variants act as a gain of function.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37338912,
title = {Suicidality Screening Guidelines Highlight the Need for Intervention Studies},
author = {Roy H Perlis},
doi = {10.1001/jamanetworkopen.2023.18773},
issn = {2574-3805},
year  = {2023},
date = {2023-06-01},
journal = {JAMA Netw Open},
volume = {6},
number = {6},
pages = {e2318773},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37262146,
title = {Rare penetrant mutations confer severe risk of common diseases},
author = {Petko P Fiziev and Jeremy McRae and Jacob C Ulirsch and Jacqueline S Dron and Tobias Hamp and Yanshen Yang and Pierrick Wainschtein and Zijian Ni and Joshua G Schraiber and Hong Gao and Dylan Cable and Yair Field and Francois Aguet and Marc Fasnacht and Ahmed Metwally and Jeffrey Rogers and Tomas Marques-Bonet and Heidi L Rehm and Anne O'Donnell-Luria and Amit V Khera and Kyle Kai-How Farh},
doi = {10.1126/science.abo1131},
issn = {1095-9203},
year  = {2023},
date = {2023-06-01},
journal = {Science},
volume = {380},
number = {6648},
pages = {eabo1131},
abstract = {We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer ~10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared with common-variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37268776,
title = {Tracking genetic variants in the biomedical literature using LitVar 2.0},
author = {Alexis Allot and Chih-Hsuan Wei and Lon Phan and Timothy Hefferon and Melissa Landrum and Heidi L Rehm and Zhiyong Lu},
doi = {10.1038/s41588-023-01414-x},
issn = {1546-1718},
year  = {2023},
date = {2023-06-01},
journal = {Nat Genet},
volume = {55},
number = {6},
pages = {901--903},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37291195,
title = {Dynamic measures of insulin action identify genetic determinants of dysglycemia},
author = {Miriam S Udler},
doi = {10.1038/s41588-023-01346-6},
issn = {1546-1718},
year  = {2023},
date = {2023-06-01},
journal = {Nat Genet},
volume = {55},
number = {6},
pages = {905--907},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36798410,
title = {Delineating regional vulnerability in the neurodegenerative disease SCA1 using a conditional mutant ATXN1 mouse},
author = {Lisa Duvick and W Michael Southern and Kellie Benzow and Zoe N Burch and Hillary P Handler and Jason S Mitchell and Hannah Kuivinen and Udaya Keerthy Gadiparthi and Praseuth Yang and Alyssa Soles and Carrie Scheeler and Orion Rainwater and Shannah Serres and Erin Lind and Tessa Nichols-Meade and Brennon O'Callaghan and Huda Y Zoghbi and Marija Cvetanovic and Vanessa C Wheeler and James M Ervasti and Michael D Koob and Harry T Orr},
doi = {10.1101/2023.02.08.527710},
year  = {2023},
date = {2023-06-01},
journal = {bioRxiv},
abstract = {Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ATXN1 protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockout mouse model (  ) having mouse  coding exons replaced by human exons encoding 146 glutamines.  mice manifest SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. CNS contributions to disease were revealed using  ;  mice, that showed improved rotarod, open field and Barnes maze performances. Striatal contributions to motor deficits were examined using  ;  mice. Mice lacking striatal  had improved rotarod performance late in disease. Muscle contributions to disease were revealed in  ;  mice which lacked muscle pathology and kyphosis seen in  mice. Kyphosis was not improved in  mice. Thus, optimal SCA1 therapeutics will require targeting mutant ATXN1 toxic actions in multiple brain regions and muscle.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37398414,
title = {Genetic and non-genetic components of family history of stroke and heart disease: a population-based study among adopted and non-adopted individuals},
author = {Ernst Mayerhofer and Livia Parodi and Kaavya Narasimhalu and Andreas Harloff and Marios K Georgakis and Jonathan Rosand and Christopher D Anderson},
doi = {10.1101/2023.05.28.23290649},
year  = {2023},
date = {2023-06-01},
journal = {medRxiv},
abstract = {BACKGROUND: It is increasingly clear that genetic and non-genetic factors account for the association of family history with disease risk in offspring. We sought to distinguish the genetic and non-genetic contributions of family history of stroke and heart disease on incident events by examining adopted and non-adopted individuals.nnMETHODS: We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495,640 participants of the UK Biobank (mean age 56.5 years, 55% female) stratified by early childhood adoption status into adoptees (n=5,747) and non-adoptees (n=489,893). We estimated hazard ratios (HRs) per affected nuclear family member, and for polygenic risk scores (PRS) for stroke and MI in Cox models adjusted for baseline age and sex.nnRESULTS: 12,518 strokes and 23,923 MIs occurred over a 13-year follow-up. In non-adoptees, family history of stroke and heart disease were associated with increased stroke and MI risk, with the strongest association of family history of stroke for incident stroke (HR 1.16 [1.12, 1.19]) and family history of heart disease for incident MI (HR 1.48 [1.45, 1.50]). In adoptees, family history of stroke associated with incident stroke (HR 1.41 [1.06, 1.86]), but family history of heart disease did not associate with incident MI (p>0.5). PRS showed strong disease-specific associations in adoptees and non-adoptees. In non-adoptees, the stroke PRS mediated 6% risk between family history of stroke and incident stroke, and the MI PRS mediated 13% risk between family history of heart disease and MI.nnCONCLUSIONS: Family history of stroke and heart disease increase risk for their respective conditions. Family history of stroke contains a substantial proportion of potentially modifiable non-genetic risk, indicating a need for further research to elucidate these elements for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37307003,
title = {Statistical and Conceptual Considerations in Socioepigenomics Research on Childhood Adversity and Epigenetic Aging},
author = {Erin C Dunn and Andrew J Simpkin and Esther Walton},
doi = {10.1001/jamanetworkopen.2023.17958},
issn = {2574-3805},
year  = {2023},
date = {2023-06-01},
journal = {JAMA Netw Open},
volume = {6},
number = {6},
pages = {e2317958},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37425837,
title = {Metabolome-wide Mendelian randomization characterizes heterogeneous and shared causal effects of metabolites on human health},
author = {Xianyong Yin and Jack Li and Debraj Bose and Jeffrey Okamoto and Annie Kwon and Anne U Jackson and Lilian Fernandes Silva and Anniina Oravilahti and Heather M Stringham and Samuli Ripatti and Mark Daly and Aarno Palotie and Laura J Scott and Charles F Burant and Eric B Fauman and Xiaoquan Wen and Michael Boehnke and Markku Laakso and Jean Morrison},
doi = {10.1101/2023.06.26.23291721},
year  = {2023},
date = {2023-06-01},
journal = {medRxiv},
abstract = {Metabolites are small molecules that are useful for estimating disease risk and elucidating disease biology. Nevertheless, their causal effects on human diseases have not been evaluated comprehensively. We performed two-sample Mendelian randomization to systematically infer the causal effects of 1,099 plasma metabolites measured in 6,136 Finnish men from the METSIM study on risk of 2,099 binary disease endpoints measured in 309,154 Finnish individuals from FinnGen. We identified evidence for 282 causal effects of 70 metabolites on 183 disease endpoints (FDR<1%). We found 25 metabolites with potential causal effects across multiple disease domains, including ascorbic acid 2-sulfate affecting 26 disease endpoints in 12 disease domains. Our study suggests that N-acetyl-2-aminooctanoate and glycocholenate sulfate affect risk of atrial fibrillation through two distinct metabolic pathways and that N-methylpipecolate may mediate the causal effect of N6, N6-dimethyllysine on anxious personality disorder. This study highlights the broad causal impact of plasma metabolites and widespread metabolic connections across diseases.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37323864,
title = {Association of Acculturation and Cardiometabolic Disease Among Immigrants of South Asian Ancestry},
author = {Nikhil Kathiresan and Amit V Khera and Aniruddh P Patel},
doi = {10.1016/j.jacasi.2023.03.006},
issn = {2772-3747},
year  = {2023},
date = {2023-06-01},
journal = {JACC Asia},
volume = {3},
number = {3},
pages = {404--406},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37013830,
title = {National Human Genome Research Institute Genomic Data Science Analysis, Visualization, and Informatics Lab-Space: Reaching out to Clinicians},
author = {Jennifer L Hall and Sally Honeycutt and Nicole Gonzalez and Anne O'Donnell-Luria and Casey Overby Taylor and Laura Stevens and Anthony A Philippakis and Michael C Schatz},
doi = {10.1161/CIRCGEN.122.003936},
issn = {2574-8300},
year  = {2023},
date = {2023-06-01},
journal = {Circ Genom Precis Med},
volume = {16},
number = {3},
pages = {275--276},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37272927,
title = {Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants},
author = {Rebecca A Rojas and Anna A Kutateladze and Lacey Plummer and Maria Stamou and David L Keefe and Kathryn B Salnikov and Angela Delaney and Janet E Hall and Ruslan Sadreyev and Fei Ji and Eric Fliers and Katarina Gambosova and Richard Quinton and Paulina M Merino and Veronica Mericq and Stephanie B Seminara and William F Crowley and Ravikumar Balasubramanian},
doi = {10.1016/j.gim.2023.100855},
issn = {1530-0366},
year  = {2023},
date = {2023-06-01},
journal = {Genet Med},
volume = {25},
number = {6},
pages = {100855},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37269009,
title = {Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis},
author = {Liang-Kun Guo and Yi Su and Yu-Ya-Nan Zhang and Hao Yu and Zhe Lu and Wen-Qiang Li and Yong-Feng Yang and Xiao Xiao and Hao Yan and Tian-Lan Lu and Jun Li and Yun-Dan Liao and Zhe-Wei Kang and Li-Fang Wang and Yue Li and Ming Li and Bing Liu and Hai-Liang Huang and Lu-Xian Lv and Yin Yao and Yun-Long Tan and Gerome Breen and Ian Everall and Hong-Xing Wang and Zhuo Huang and Dai Zhang and Wei-Hua Yue},
doi = {10.1186/s40779-023-00459-7},
issn = {2054-9369},
year  = {2023},
date = {2023-06-01},
journal = {Mil Med Res},
volume = {10},
number = {1},
pages = {24},
abstract = {BACKGROUND: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment.nnMETHODS: Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R for regression, and decision curve analysis.nnRESULTS: Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R = 0.507].nnCONCLUSIONS: This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36805433,
title = {Teaching NeuroImage: Subacute Quadriparesis From Intramedullary Spinal Cord Infiltrating Glioma With  Promoter Mutation},
author = {Simon Gritsch and Yasmin Aghajan and Liana Kozanno and Daniel Chiu and Justin T Jordan and Matthew P Frosch and Ganesh Shankar and W Taylor Kimberly},
doi = {10.1212/WNL.0000000000207148},
issn = {1526-632X},
year  = {2023},
date = {2023-06-01},
journal = {Neurology},
volume = {100},
number = {24},
pages = {1164--1165},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37316112,
title = {Reduced Stress-Related Neural Network Activity Mediates the Effect of Alcohol on Cardiovascular Risk},
author = {Kenechukwu Mezue and Michael T Osborne and Shady Abohashem and Hadil Zureigat and Charbel Gharios and Simran S Grewal and Azar Radfar and Alexander Cardeiro and Taimur Abbasi and Karmel W Choi and Zahi A Fayad and Jordan W Smoller and Rachel Rosovsky and Lisa Shin and Roger Pitman and Ahmed Tawakol},
doi = {10.1016/j.jacc.2023.04.015},
issn = {1558-3597},
year  = {2023},
date = {2023-06-01},
journal = {J Am Coll Cardiol},
volume = {81},
number = {24},
pages = {2315--2325},
abstract = {BACKGROUND: Chronic stress associates with major adverse cardiovascular events (MACE) via increased stress-related neural network activity (SNA). Light/moderate alcohol consumption (AC) has been linked to lower MACE risk, but the mechanisms are unclear.nnOBJECTIVES: The purpose of this study was to evaluate whether the association between AC and MACE is mediated by decreased SNA.nnMETHODS: Individuals enrolled in the Mass General Brigham Biobank who completed a health behavior survey were studied. A subset underwent F-fluorodeoxyglucose positron emission tomography, enabling assessment of SNA. Alcohol consumption was classified as none/minimal, light/moderate, or high (<1, 1-14, or >14 drinks/week, respectively).nnRESULTS: Of 53,064 participants (median age 60 years, 60% women), 23,920 had no/minimal alcohol consumption and 27,053 AC. Over a median follow-up of 3.4 years, 1,914 experienced MACE. AC (vs none/minimal) associated with lower MACE risk (HR: 0.786; 95% CI: 0.717-0.862; P < 0.0001) after adjusting for cardiovascular risk factors. In 713 participants with brain imaging, AC (vs none/minimal) associated with decreased SNA (standardized beta -0.192; 95% CI: -0.338 to -0.046; P = 0.01). Lower SNA partially mediated the beneficial effect of AC on MACE (log OR: -0.040; 95% CI: -0.097 to -0.003; P < 0.05). Further, AC associated with larger decreases in MACE risk among individuals with (vs without) prior anxiety (HR: 0.60 [95% CI: 0.50-0.72] vs 0.78 [95% CI: 0.73-0.80]; P interaction = 0.003).nnCONCLUSIONS: AC associates with reduced MACE risk, in part, by lowering activity of a stress-related brain network known for its association with cardiovascular disease. Given alcohol's potential health detriments, new interventions with similar effects on SNA are needed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37021483,
title = {Specific miRNAs are associated with human cancer cachexia in an organ-specific manner},
author = {Tanja Krauss and Simone Heisz and Julius Honecker and Olga Prokopchuk and Marc Martignoni and Klaus-Peter Janssen and Melina Claussnitzer and Hans Hauner and Claudine Seeliger},
doi = {10.1002/jcsm.13224},
issn = {2190-6009},
year  = {2023},
date = {2023-06-01},
journal = {J Cachexia Sarcopenia Muscle},
volume = {14},
number = {3},
pages = {1381--1394},
abstract = {BACKGROUND: Cancer cachexia (CCx) is a complex and multi-organ wasting syndrome characterized by substantial weight loss and poor prognosis. An improved understanding of the mechanisms involved in the onset and progression of cancer cachexia is essential. How microRNAs contribute to the clinical manifestation and progression of CCx remains elusive. The aim of this study was to identify specific miRNAs related to organ-specific CCx and explore their functional role in humans.nnMETHODS: miRNA patterns in serum and in cachexia target organs (liver, muscle and adipose tissue) from weight stable (N ≤ 12) and cachectic patients (N ≤ 23) with gastrointestinal cancer were analysed. As a first step, a miRNA array (158 miRNAs) was performed in pooled serum samples. Identified miRNAs were validated in serum and corresponding tissue samples. Using in silico prediction, related genes were identified and evaluated. The findings were confirmed in vitro by siRNA knock-down experiments in human visceral preadipocytes and C2C12 myoblast cells and consecutive gene expression analyses.nnRESULTS: Validating the results of the array, a 2-fold down-regulation of miR-122-5p (P = 0.0396) and a 4.5-fold down-regulation of miR-194-5p (P < 0.0001) in serum of CCx patients in comparison with healthy controls were detected. Only miR-122-5p correlated with weight loss and CCx status (P = 0.0367). Analysing corresponding tissues six muscle and eight visceral adipose tissue (VAT) cachexia-associated miRNAs were identified. miR-27b-3p, miR-375 and miR-424-5p were the most consistently affected miRNAs in tissues of CCx patients correlating negatively with the severity of body weight loss (P = 0.0386, P = 0.0112 and P = 0.0075, respectively). We identified numerous putative target genes of the miRNAs in association with muscle atrophy and lipolysis pathways. Knock-down experiments in C2C12 myoblast cells revealed an association of miR-27b-3p and the in silico predicted atrophy-related target genes IL-15 and TRIM63. Both were up-regulated in miR-27b-3p knock-down cells (P < 0.05). Concordantly, in muscle tissue of CCx individuals, significant higher expression levels of IL-15 (P = 0.0237) and TRIM63 (P = 0.0442) were detected. miR-424-5p was identified to regulate the expression of lipase genes. Knock-down experiments in human visceral preadipocytes revealed an inverse association of miR-424-5p with its predicted target genes LIPE, PNPLA2, MGLL and LPL (P < 0.01).nnCONCLUSIONS: The identified miRNAs, in particular miR-122-5p, miR-27b-3p, miR-375 and miR-424-5p, represent features of human CCx and may contribute to tissue wasting and skeletal muscle atrophy through the regulation of catabolic signals. Further studies are needed to explore the potential of the identified miRNAs as a screening tool for early detection of cancer cachexia.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37289866,
title = {Taurine deficiency as a driver of aging},
author = {Parminder Singh and Kishore Gollapalli and Stefano Mangiola and Daniela Schranner and Mohd Aslam Yusuf and Manish Chamoli and Sting L Shi and Bruno Lopes Bastos and Tripti Nair and Annett Riermeier and Elena M Vayndorf and Judy Z Wu and Aishwarya Nilakhe and Christina Q Nguyen and Michael Muir and Michael G Kiflezghi and Anna Foulger and Alex Junker and Jack Devine and Kunal Sharan and Shankar J Chinta and Swati Rajput and Anand Rane and Philipp Baumert and Martin Schönfelder and Francescopaolo Iavarone and Giorgia di Lorenzo and Swati Kumari and Alka Gupta and Rajesh Sarkar and Costerwell Khyriem and Amanpreet S Chawla and Ankur Sharma and Nazan Sarper and Naibedya Chattopadhyay and Bichitra K Biswal and Carmine Settembre and Perumal Nagarajan and Kimara L Targoff and Martin Picard and Sarika Gupta and Vidya Velagapudi and Anthony T Papenfuss and Alaattin Kaya and Miguel Godinho Ferreira and Brian K Kennedy and Julie K Andersen and Gordon J Lithgow and Abdullah Mahmood Ali and Arnab Mukhopadhyay and Aarno Palotie and Gabi Kastenmüller and Matt Kaeberlein and Henning Wackerhage and Bhupinder Pal and Vijay K Yadav},
doi = {10.1126/science.abn9257},
issn = {1095-9203},
year  = {2023},
date = {2023-06-01},
journal = {Science},
volume = {380},
number = {6649},
pages = {eabn9257},
abstract = {Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37292704,
title = {Convergent imaging-transcriptomic evidence for disturbed iron homeostasis in Gilles de la Tourette syndrome},
author = {Ahmad Seif Kanaan and Dongmei Yu and Riccardo Metere and Andreas Schäfer and Torsten Schlumm and Berkin Bilgic and Alfred Anwander and Carol A Mathews and Jeremiah M Scharf and Kirsten Müller-Vahl and Harald E Möller},
doi = {10.1101/2023.05.15.23289978},
year  = {2023},
date = {2023-05-01},
journal = {medRxiv},
abstract = {Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patient cohort, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns extracted from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron-sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms that affect receptor expression and long-term potentiation. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37140408,
title = {Evening types as determined by subjective and objective measures are more emotional eaters},
author = {Marta Garaulet and Barbara Vizmanos and Teresa Muela and Alejandra Betancourt-Núñez and María-Ángeles Bonmatí-Carrión and Céline Vetter and Hassan S Dashti and Richa Saxena and Frank A J L Scheer},
doi = {10.1002/oby.23749},
issn = {1930-739X},
year  = {2023},
date = {2023-05-01},
journal = {Obesity (Silver Spring)},
volume = {31},
number = {5},
pages = {1192--1203},
abstract = {OBJECTIVE: This study aimed to determine the association between being an evening type (ET; defined subjectively by the Morning-Evening Questionnaire or objectively by the dim-light melatonin onset [DLMO] timing) and reporting emotional eating (EE) behaviors.nnMETHODS: Cross-sectional analyses were conducted in 3964 participants (four international cohorts: ONTIME and ONTIME-MT [both Spain], SHIFT [the US], and DICACEM [Mexico]), in which chronotype (Morning-Evening Questionnaire), EE behaviors (Emotional Eating Questionnaire), and dietary habits (dietary records or food-frequency questionnaire) were assessed. Among 162 participants (ONTIME-MT subsample), additional measures of DLMO (physiological gold standard of circadian phase) were available.nnRESULTS: In three populations, ETs presented with a higher EE score than morning types (p < 0.02); and they made up a higher proportion of emotional eaters (p < 0.01). ETs presented with higher scores on disinhibition/overeating as well as food craving factors and experienced these behaviors more frequently than morning types (p < 0.05). Furthermore, a meta-analysis showed that being an ET was associated with a higher EE score by 1.52 points of a total of 30 points (95% CI: 0.89-2.14). The timing of DLMO in the early, intermediate, and late objective chronotypes occurred at 21:02 h, 22:12 h, and 23:37 h, with late types showing a higher EE score (p = 0.043).nnCONCLUSIONS: Eveningness associated with EE in populations with different cultural, environmental, and genetic backgrounds. Individuals with late DLMO also showed more EE.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37137588,
title = {Lipoprotein(a), Oxidized Phospholipids, and Coronary Artery Disease Severity and Outcomes},
author = {Thomas C Gilliland and Yuxi Liu and Reza Mohebi and Hannah Miksenas and Sara Haidermota and Megan Wong and Xingdi Hu and Joaquim Rosado Cristino and Auris Browne and Jorge Plutzky and Sotirios Tsimikas and James L Januzzi and Pradeep Natarajan},
doi = {10.1016/j.jacc.2023.02.050},
issn = {1558-3597},
year  = {2023},
date = {2023-05-01},
journal = {J Am Coll Cardiol},
volume = {81},
number = {18},
pages = {1780--1792},
abstract = {BACKGROUND: Lipoprotein(a) (Lp[a]) and oxidized phospholipids (OxPLs) are each independent risk factors for atherosclerotic cardiovascular disease. The extent to which Lp(a) and OxPLs predict coronary artery disease (CAD) severity and outcomes in a contemporary, statin-treated cohort is not well established.nnOBJECTIVES: This study sought to evaluate the relationships between Lp(a) particle concentration and OxPLs associated with apolipoprotein B (OxPL-apoB) or apolipoprotein(a) (OxPL-apo[a]) with angiographic CAD and cardiovascular outcomes.nnMETHODS: Among 1,098 participants referred for coronary angiography in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study, Lp(a), OxPL-apoB, and OxPL-apo(a) were measured. Logistic regression estimated the risk of multivessel coronary stenoses by Lp(a)-related biomarker level. Cox proportional hazards regression estimated the risk of major adverse cardiovascular events (MACEs) (coronary revascularization, nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) in follow-up.nnRESULTS: Median Lp(a) was 26.45 nmol/L (IQR: 11.39-89.49 nmol/L). Lp(a), OxPL-apoB, and OxPL-apo(a) were highly correlated (Spearman R ≥0.91 for all pairwise combinations). Lp(a) and OxPL-apoB were associated with multivessel CAD. Odds of multivessel CAD per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.10 (95% CI: 1.03-1.18; P = 0.006), 1.18 (95% CI: 1.03-1.34; P = 0.01), and 1.07 (95% CI: 0.99-1.16; P = 0.07), respectively. All biomarkers were associated with cardiovascular events. HRs for MACE per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.08 (95% CI: 1.03-1.14; P = 0.001), 1.15 (95% CI: 1.05-1.26; P = 0.004), and 1.07 (95% CI: 1.01-1.14; P = 0.02), respectively.nnCONCLUSIONS: In patients undergoing coronary angiography, Lp(a) and OxPL-apoB are associated with multivessel CAD. Lp(a), OxPL-apoB, and OxPL-apo(a) are associated with incident cardiovascular events. (Catheter Sampled Blood Archive in Cardiovascular Diseases [CASABLANCA]; NCT00842868).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37143087,
title = {Investigating the relationship between depression and breast cancer: observational and genetic analyses},
author = {Xueyao Wu and Wenqiang Zhang and Xunying Zhao and Li Zhang and Minghan Xu and Yu Hao and Jinyu Xiao and Ben Zhang and Jiayuan Li and Peter Kraft and Jordan W Smoller and Xia Jiang},
doi = {10.1186/s12916-023-02876-w},
issn = {1741-7015},
year  = {2023},
date = {2023-05-01},
journal = {BMC Med},
volume = {21},
number = {1},
pages = {170},
abstract = {BACKGROUND: Both depression and breast cancer (BC) contribute to a substantial global burden of morbidity and mortality among women, and previous studies have observed a potential depression-BC link. We aimed to comprehensively characterize the phenotypic and genetic relationships between depression and BC.nnMETHODS: We first evaluated phenotypic association using longitudinal follow-up data from the UK Biobank (N = 250,294). We then investigated genetic relationships leveraging summary statistics from the hitherto largest genome-wide association study of European individuals conducted for depression (N = 500,199), BC (N = 247,173), and its subtypes based on the status of estrogen receptor (ER + : N = 175,475; ER - : N = 127,442).nnRESULTS: Observational analysis suggested an increased hazard of BC in depression patients (HR = 1.10, 95%CIs = 0.95-1.26). A positive genetic correlation between depression and overall BC was observed ([Formula: see text] = 0.08, P = 3.00 × 10), consistent across ER + ([Formula: see text] = 0.06, P = 6.30 × 10) and ER - subtypes ([Formula: see text] = 0.08, P = 7.20 × 10). Several specific genomic regions showed evidence of local genetic correlation, including one locus at 9q31.2, and four loci at, or close, to 6p22.1. Cross-trait meta-analysis identified 17 pleiotropic loci shared between depression and BC. TWAS analysis revealed five shared genes. Bi-directional Mendelian randomization suggested risk of depression was causally associated with risk of overall BC (OR = 1.12, 95%Cis = 1.04-1.19), but risk of BC was not causally associated with risk of depression.nnCONCLUSIONS: Our work demonstrates a shared genetic basis, pleiotropic loci, and a putative causal relationship between depression and BC, highlighting a biological link underlying the observed phenotypic relationship; these findings may provide important implications for future studies aimed reducing BC risk.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37156999,
title = {Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries},
author = {Zhanju Liu and Ruize Liu and Han Gao and Seulgi Jung and Xiang Gao and Ruicong Sun and Xiaoming Liu and Yongjae Kim and Ho-Su Lee and Yosuke Kawai and Masao Nagasaki and Junji Umeno and Katsushi Tokunaga and Yoshitaka Kinouchi and Atsushi Masamune and Wenzhao Shi and Chengguo Shen and Zhenglin Guo and Kai Yuan and  and  and  and Shu Zhu and Dalin Li and Jianjun Liu and Tian Ge and Judy Cho and Mark J Daly and Dermot P B McGovern and Byong Duk Ye and Kyuyoung Song and Yoichi Kakuta and Mingsong Li and Hailiang Huang},
doi = {10.1038/s41588-023-01384-0},
issn = {1546-1718},
year  = {2023},
date = {2023-05-01},
journal = {Nat Genet},
volume = {55},
number = {5},
pages = {796--806},
abstract = {Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2. Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency (NOD2) and effect (TNFSF15). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37003169,
title = {An efficient landmark model for prediction of suicide attempts in multiple clinical settings},
author = {Yi-Han Sheu and Jiehuan Sun and Hyunjoon Lee and Victor M Castro and Yuval Barak-Corren and Eugene Song and Emily M Madsen and William J Gordon and Isaac S Kohane and Susanne E Churchill and Ben Y Reis and Tianxi Cai and Jordan W Smoller},
doi = {10.1016/j.psychres.2023.115175},
issn = {1872-7123},
year  = {2023},
date = {2023-05-01},
journal = {Psychiatry Res},
volume = {323},
pages = {115175},
abstract = {Growing evidence has shown that applying machine learning models to large clinical data sources may exceed clinician performance in suicide risk stratification. However, many existing prediction models either suffer from "temporal bias" (a bias that stems from using case-control sampling) or require training on all available patient visit data. Here, we adopt a "landmark model" framework that aligns with clinical practice for prediction of suicide-related behaviors (SRBs) using a large electronic health record database. Using the landmark approach, we developed models for SRB prediction (regularized Cox regression and random survival forest) that establish a time-point (e.g., clinical visit) from which predictions are made over user-specified prediction windows using historical information up to that point. We applied this approach to cohorts from three clinical settings: general outpatient, psychiatric emergency department, and psychiatric inpatients, for varying prediction windows and lengths of historical data. Models achieved high discriminative performance (area under the Receiver Operating Characteristic curve 0.74-0.93 for the Cox model) across different prediction windows and settings, even with relatively short periods of historical data. In short, we developed accurate, dynamic SRB risk prediction models with the landmark approach that reduce bias and enhance the reliability and portability of suicide risk prediction models.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36791419,
title = {Investigating Gene-Diet Interactions Impacting the Association Between Macronutrient Intake and Glycemic Traits},
author = {Kenneth E Westerman and Maura E Walker and Sheila M Gaynor and Jennifer Wessel and Daniel DiCorpo and Jiantao Ma and Alvaro Alonso and Stella Aslibekyan and Abigail S Baldridge and Alain G Bertoni and Mary L Biggs and Jennifer A Brody and Yii-Der Ida Chen and Joseé Dupuis and Mark O Goodarzi and Xiuqing Guo and Natalie R Hasbani and Adam Heath and Bertha Hidalgo and Marguerite R Irvin and W Craig Johnson and Rita R Kalyani and Leslie Lange and Rozenn N Lemaitre and Ching-Ti Liu and Simin Liu and Jee-Young Moon and Rami Nassir and James S Pankow and Mary Pettinger and Laura M Raffield and Laura J Rasmussen-Torvik and Elizabeth Selvin and Mackenzie K Senn and Aladdin H Shadyab and Albert V Smith and Nicholas L Smith and Lyn Steffen and Sameera Talegakwar and Kent D Taylor and Paul S de Vries and James G Wilson and Alexis C Wood and Lisa R Yanek and Jie Yao and Yinan Zheng and Eric Boerwinkle and Alanna C Morrison and Miriam Fornage and Tracy P Russell and Bruce M Psaty and Daniel Levy and Nancy L Heard-Costa and Vasan S Ramachandran and Rasika A Mathias and Donna K Arnett and Robert Kaplan and Kari E North and Adolfo Correa and April Carson and Jerome I Rotter and Stephen S Rich and JoAnn E Manson and Alexander P Reiner and Charles Kooperberg and Jose C Florez and James B Meigs and Jordi Merino and Deirdre K Tobias and Han Chen and Alisa K Manning},
doi = {10.2337/db22-0851},
issn = {1939-327X},
year  = {2023},
date = {2023-05-01},
journal = {Diabetes},
volume = {72},
number = {5},
pages = {653--665},
abstract = {Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g., for glycated hemoglobin [HbA1c], -0.013% HbA1c/250 kcal substitution). In GDI meta-analyses, a common African ancestry-enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate-HbA1c association among major allele homozygotes only. Simulations revealed that >150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry.nnARTICLE HIGHLIGHTS: We aimed to identify genetic modifiers of the dietary macronutrient-glycemia relationship using whole-genome sequence data from 10 Trans-Omics for Precision Medicine program cohorts. Substitution models indicated a modest reduction in glycemia associated with an increase in dietary carbohydrate at the expense of fat. Genome-wide interaction analysis identified one African ancestry-enriched variant near the FRAS1 gene that may interact with macronutrient intake to influence hemoglobin A1c. Simulation-based power calculations accounting for measurement error suggested that substantially larger sample sizes may be necessary to discover further gene-macronutrient interactions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36705326,
title = {Migraine, inflammatory bowel disease and celiac disease: A Mendelian randomization study},
author = {Nike Zoe Welander and Gull Rukh and Mathias Rask-Andersen and Aster V E Harder and  and Arn M J M van den Maagdenberg and Helgi Birgir Schiöth and Jessica Mwinyi},
doi = {10.1111/head.14470},
issn = {1526-4610},
year  = {2023},
date = {2023-05-01},
journal = {Headache},
volume = {63},
number = {5},
pages = {642--651},
abstract = {OBJECTIVE: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.nnBACKGROUND: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition.nnMETHODS: Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed.nnRESULTS: Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction.nnCONCLUSIONS: We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36652671,
title = {A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic data sets},
author = {Caitlyn Vlasschaert and Taralynn Mack and J Brett Heimlich and Abhishek Niroula and Md Mesbah Uddin and Joshua Weinstock and Brian Sharber and Alexander J Silver and Yaomin Xu and Michael Savona and Christopher Gibson and Matthew B Lanktree and Michael J Rauh and Benjamin L Ebert and Pradeep Natarajan and Siddhartha Jaiswal and Alexander G Bick},
doi = {10.1182/blood.2022018825},
issn = {1528-0020},
year  = {2023},
date = {2023-05-01},
journal = {Blood},
volume = {141},
number = {18},
pages = {2214--2223},
abstract = {Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples that are sequenced using approaches that cover the whole genome, the whole exome, or targeted genetic regions; however, differentiating true CHIP mutations from sequencing artifacts and germ line variants is a considerable bioinformatic challenge. We present a stepwise method that combines filtering based on sequencing metrics, variant annotation, and population-based associations to increase the accuracy of CHIP calls. We apply this approach to ascertain CHIP in ∼550 000 individuals in the UK Biobank complete whole exome cohort and the All of Us Research Program initial whole genome release cohort. CHIP ascertainment on this scale unmasks recurrent artifactual variants and highlights the importance of specialized filtering approaches for several genes, including TET2 and ASXL1. We show how small changes in filtering parameters can considerably increase CHIP misclassification and reduce the effect size of epidemiological associations. Our high-fidelity call set refines previous population-based associations of CHIP with incident outcomes. For example, the annualized incidence of myeloid malignancy in individuals with small CHIP clones is 0.03% per year, which increases to 0.5% per year among individuals with very large CHIP clones. We also find a significantly lower prevalence of CHIP in individuals of self-reported Latino or Hispanic ethnicity in All of Us, highlighting the importance of including diverse populations. The standardization of CHIP calling will increase the fidelity of CHIP epidemiological work and is required for clinical CHIP diagnostic assays.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36893755,
title = {Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus},
author = {Cameron Sadegh and Huixin Xu and Jason Sutin and Benoit Fatou and Suhasini Gupta and Aja Pragana and Milo Taylor and Peter N Kalugin and Miriam E Zawadzki and Osama Alturkistani and Frederick B Shipley and Neil Dani and Ryann M Fame and Zainab Wurie and Pratik Talati and Riana L Schleicher and Eric M Klein and Yong Zhang and Michael J Holtzman and Christopher I Moore and Pei-Yi Lin and Aman B Patel and Benjamin C Warf and W Taylor Kimberly and Hanno Steen and Mark L Andermann and Maria K Lehtinen},
doi = {10.1016/j.neuron.2023.02.020},
issn = {1097-4199},
year  = {2023},
date = {2023-05-01},
journal = {Neuron},
volume = {111},
number = {10},
pages = {1591--1608.e4},
abstract = {Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36315648,
title = {The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15},
author = {Afshin Saffari and Melanie Kellner and Catherine Jordan and Helena Rosengarten and Alisa Mo and Bo Zhang and Oleksandr Strelko and Sonja Neuser and Marie Y Davis and Nobuaki Yoshikura and Naonobu Futamura and Tomoya Takeuchi and Shin Nabatame and Hiroyuki Ishiura and Shoji Tsuji and Huda Shujaa Aldeen and Elisa Cali and Clarissa Rocca and Henry Houlden and Stephanie Efthymiou and Birgit Assmann and Grace Yoon and Bianca A Trombetta and Pia Kivisäkk and Florian Eichler and Haitian Nan and Yoshihisa Takiyama and Alessandra Tessa and Filippo M Santorelli and Mustafa Sahin and Craig Blackstone and Edward Yang and Rebecca Schüle and Darius Ebrahimi-Fakhari},
doi = {10.1093/brain/awac391},
issn = {1460-2156},
year  = {2023},
date = {2023-05-01},
journal = {Brain},
volume = {146},
number = {5},
pages = {2003--2015},
abstract = {In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36734038,
title = {Plasma protein and venous thromboembolism: prospective cohort and mendelian randomisation analyses},
author = {Shuai Yuan and Olga E Titova and Ke Zhang and Wanglong Gou and Tessa Schillemans and Pradeep Natarajan and Jie Chen and Xue Li and Agneta Åkesson and Maria Bruzelius and Derek Klarin and Scott M Damrauer and Susanna C Larsson},
doi = {10.1111/bjh.18679},
issn = {1365-2141},
year  = {2023},
date = {2023-05-01},
journal = {Br J Haematol},
volume = {201},
number = {4},
pages = {783--792},
abstract = {We conducted cohort and Mendelian randomisation (MR) analyses to examine the associations of circulating proteins with risk of venous thromboembolism (VTE) to provide evidence basis for disease prevention and drug development. Cohort analysis was performed in 11 803 participants without baseline VTE. Cox regression was used to estimate the associations between 257 proteins and VTE risk. A machine-learning model was constructed to compare the importance of identified proteins and traditional risk factors. Genetic association data on VTE were obtained from a genome-wide meta-analysis (26 066 cases and 624 053 controls) and FinnGen (14 454 cases and 294 700 controls). The cohort analysis, including 353 incident VTE cases diagnosed during a 6.6-year follow-up, identified 21 proteins associated with VTE risk after false discovery rate correction. The machine-learning model indicated that body mass index and von Willebrand factor (vWF) made the same as well as most of the contributions to the overall model prediction. MR analysis found that genetically predicted levels of vWF, SERPINE1 (plasminogen activator inhibitor 1, known as PAI-1), EPHB4 (ephrin type-B receptor 4), TYRO3 (tyrosine-protein kinase receptor TYRO3), TNFRSF11A (tumour necrosis factor receptor superfamily member 11A), and BOC (brother of CDO) were causally associated with VTE risk.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36720639,
title = {Future of Neurology & Technology: Neuroimaging Made Accessible Using Low-Field, Portable MRI},
author = {Nethra R Parasuram and Anna L Crawford and Mercy H Mazurek and Isha R Chavva and Rachel Beekman and Emily J Gilmore and Nils H Petersen and Seyedmehdi Payabvash and Gordon Sze and Juan Eugenio Iglesias and Sacit B Omay and Charles Matouk and Erin E Longbrake and Adam de Havenon and Steven J Schiff and Matthew S Rosen and W Taylor Kimberly and Kevin N Sheth},
doi = {10.1212/WNL.0000000000207074},
issn = {1526-632X},
year  = {2023},
date = {2023-05-01},
journal = {Neurology},
volume = {100},
number = {22},
pages = {1067--1071},
abstract = {In the 20th century, the advent of neuroimaging dramatically altered the field of neurologic care. However, despite iterative advances since the invention of CT and MRI, little progress has been made to bring MR neuroimaging to the point of care. Recently, the emergence of a low-field (<1 T) portable MRI (pMRI) is setting the stage to revolutionize the landscape of accessible neuroimaging. Users can transport the pMRI into a variety of locations, using a standard 110-220 V wall outlet. In this article, we discuss current applications for pMRI, including in the acute and critical care settings, the barriers to broad implementation, and future opportunities.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37220109,
title = {Hypoxia extends lifespan and neurological function in a mouse model of aging},
author = {Robert S Rogers and Hong Wang and Timothy J Durham and Jonathan A Stefely and Norah A Owiti and Andrew L Markhard and Lev Sandler and Tsz-Leung To and Vamsi K Mootha},
doi = {10.1371/journal.pbio.3002117},
issn = {1545-7885},
year  = {2023},
date = {2023-05-01},
journal = {PLoS Biol},
volume = {21},
number = {5},
pages = {e3002117},
abstract = {There is widespread interest in identifying interventions that extend healthy lifespan. Chronic continuous hypoxia delays the onset of replicative senescence in cultured cells and extends lifespan in yeast, nematodes, and fruit flies. Here, we asked whether chronic continuous hypoxia is beneficial in mammalian aging. We utilized the Ercc1 Δ/- mouse model of accelerated aging given that these mice are born developmentally normal but exhibit anatomic, physiological, and biochemical features of aging across multiple organs. Importantly, they exhibit a shortened lifespan that is extended by dietary restriction, the most potent aging intervention across many organisms. We report that chronic continuous 11% oxygen commenced at 4 weeks of age extends lifespan by 50% and delays the onset of neurological debility in Ercc1 Δ/- mice. Chronic continuous hypoxia did not impact food intake and did not significantly affect markers of DNA damage or senescence, suggesting that hypoxia did not simply alleviate the proximal effects of the Ercc1 mutation, but rather acted downstream via unknown mechanisms. To the best of our knowledge, this is the first study to demonstrate that "oxygen restriction" can extend lifespan in a mammalian model of aging.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36695634,
title = {Genome-Wide Analysis of Structural Variants in Parkinson Disease},
author = {Kimberley J Billingsley and Jinhui Ding and Pilar Alvarez Jerez and Anastasia Illarionova and Kristin Levine and Francis P Grenn and Mary B Makarious and Anni Moore and Daniel Vitale and Xylena Reed and Dena Hernandez and Ali Torkamani and Mina Ryten and John Hardy and  and Ruth Chia and Sonja W Scholz and Bryan J Traynor and Clifton L Dalgard and Debra J Ehrlich and Toshiko Tanaka and Luigi Ferrucci and Thomas G Beach and Geidy E Serrano and John P Quinn and Vivien J Bubb and Ryan L Collins and Xuefang Zhao and Mark Walker and Emma Pierce-Hoffman and Harrison Brand and Michael E Talkowski and Bradford Casey and Mark R Cookson and Androo Markham and Mike A Nalls and Medhat Mahmoud and Fritz J Sedlazeck and Cornelis Blauwendraat and J Raphael Gibbs and Andrew B Singleton},
doi = {10.1002/ana.26608},
issn = {1531-8249},
year  = {2023},
date = {2023-05-01},
journal = {Ann Neurol},
volume = {93},
number = {5},
pages = {1012--1022},
abstract = {OBJECTIVE: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.nnMETHODS: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data.nnRESULTS: We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4.nnINTERPRETATION: We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023;93:1012-1022.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37014069,
title = {Causal effect of adiposity on the risk of 19 gastrointestinal diseases: a Mendelian randomization study},
author = {Min Seo Kim and Minku Song and Soyeon Kim and Beomsu Kim and Wonseok Kang and Jong Yeob Kim and Woojae Myung and Inhyeok Lee and Ron Do and Amit V Khera and Hong-Hee Won},
doi = {10.1002/oby.23722},
issn = {1930-739X},
year  = {2023},
date = {2023-05-01},
journal = {Obesity (Silver Spring)},
volume = {31},
number = {5},
pages = {1436--1444},
abstract = {OBJECTIVE: Although the association between adiposity and gastrointestinal (GI) diseases has been explored, the causal effects of adiposity on GI diseases are largely unknown.nnMETHODS: Mendelian randomization was conducted using single-nucleotide polymorphisms associated with BMI and waist circumference (WC) as instrumental variables, and the causal associations of BMI or WC with GI conditions were estimated among >400,000 UK Biobank participants, >170,000 Finnish-descent participants, and numerous consortia participants of predominantly European ancestry.nnRESULTS: Genetically predicted BMI was robustly associated with increased risk of nonalcoholic fatty liver disease (NAFLD), cholecystitis, cholelithiasis, and primary biliary cholangitis. For the diseases, the odds ratio per 1-SD increase in genetically predicted BMI (4.77 kg/m ) ranged from 1.22 (95% CI: 1.12-1.34; p < 0.0001) for NAFLD to 1.65 (95% CI: 1.31-2.06; p < 0.0001) for cholecystitis. Genetically predicted WC was robustly associated with increased risk of NAFLD, alcoholic liver disease, cholecystitis, cholelithiasis, colon cancer, and gastric cancer. Alcoholic liver disease was consistently associated with WC even after adjusting for alcohol consumption in a multivariable Mendelian randomization analysis. The odds ratio per 1-SD increase in genetically predicted WC (12.52 cm) for such associations ranged from 1.41 (95% CI: 1.17-1.70; p = 0.0015) for gastric cancer to 1.74 (95% CI: 1.21-1.78; p < 0.0001) for cholelithiasis.nnCONCLUSIONS: High genetically predicted adiposity was causally associated with an increased risk of GI abnormalities, particularly of hepatobiliary organs (liver, biliary tract, and gallbladder) that are functionally related to fat metabolism.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37075753,
title = {FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity},
author = {Nicolas Wieder and Juliana Coraor Fried and Choah Kim and Eriene-Heidi Sidhom and Matthew R Brown and Jamie L Marshall and Carlos Arevalo and Moran Dvela-Levitt and Maria Kost-Alimova and Jonas Sieber and Katlyn R Gabriel and Julian Pacheco and Clary Clish and Hamdah Shafqat Abbasi and Shantanu Singh and Justine C Rutter and Martine Therrien and Haejin Yoon and Zon Weng Lai and Aaron Baublis and Renuka Subramanian and Ranjan Devkota and Jonnell Small and Vedagopuram Sreekanth and Myeonghoon Han and Donghyun Lim and Anne E Carpenter and Jason Flannick and Hilary Finucane and Marcia C Haigis and Melina Claussnitzer and Eric Sheu and Beth Stevens and Bridget K Wagner and Amit Choudhary and Jillian L Shaw and Juan Lorenzo Pablo and Anna Greka},
doi = {10.1016/j.cmet.2023.03.018},
issn = {1932-7420},
year  = {2023},
date = {2023-05-01},
journal = {Cell Metab},
volume = {35},
number = {5},
pages = {887--905.e11},
abstract = {Cellular exposure to free fatty acids (FFAs) is implicated in the pathogenesis of obesity-associated diseases. However, there are no scalable approaches to comprehensively assess the diverse FFAs circulating in human plasma. Furthermore, assessing how FFA-mediated processes interact with genetic risk for disease remains elusive. Here, we report the design and implementation of fatty acid library for comprehensive ontologies (FALCON), an unbiased, scalable, and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids associated with decreased membrane fluidity. Furthermore, we prioritized genes that reflect the combined effects of harmful FFA exposure and genetic risk for type 2 diabetes (T2D). We found that c-MAF-inducing protein (CMIP) protects cells from FFA exposure by modulating Akt signaling. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37054711,
title = {Bi-allelic variants in INTS11 are associated with a complex neurological disorder},
author = {Burak Tepe and Erica L Macke and Marcello Niceta and Monika Weisz Hubshman and Oguz Kanca and Laura Schultz-Rogers and Yuri A Zarate and G Bradley Schaefer and Jorge Luis Granadillo De Luque and Daniel J Wegner and Benjamin Cogne and Brigitte Gilbert-Dussardier and Xavier Le Guillou and Eric J Wagner and Lynn S Pais and Jennifer E Neil and Ganeshwaran H Mochida and Christopher A Walsh and Nurit Magal and Valerie Drasinover and Mordechai Shohat and Tanya Schwab and Chris Schmitz and Karl Clark and Anthony Fine and Brendan Lanpher and Ralitza Gavrilova and Pierre Blanc and Lydie Burglen and Alexandra Afenjar and Dora Steel and Manju A Kurian and Prab Prabhakar and Sophie Gößwein and Nataliya Di Donato and Enrico S Bertini and  and Michael F Wangler and Shinya Yamamoto and Marco Tartaglia and Eric W Klee and Hugo J Bellen},
doi = {10.1016/j.ajhg.2023.03.012},
issn = {1537-6605},
year  = {2023},
date = {2023-05-01},
journal = {Am J Hum Genet},
volume = {110},
number = {5},
pages = {774--789},
abstract = {The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37483562,
title = {Prediction of risk for myeloid malignancy in clonal hematopoiesis},
author = {Lachelle D Weeks and Abhishek Niroula and Donna Neuberg and Waihay Wong and R Coleman Lindsley and Marlise Luskin and Nancy Berliner and Richard M Stone and Daniel J DeAngelo and Robert Soiffer and Md Mesbah Uddin and Gabriel Griffin and Caitlyn Vlasschaert and Christopher J Gibson and Siddhartha Jaiswal and Alexander G Bick and Luca Malcovati and Pradeep Natarajan and Benjamin L Ebert},
doi = {10.1056/evidoa2200310},
issn = {2766-5526},
year  = {2023},
date = {2023-05-01},
journal = {NEJM Evid},
volume = {2},
number = {5},
abstract = {BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) ≥ 0.02, in the absence and presence of cytopenia, respectively. CHIP/CCUS is highly prevalent in adults and defining predictors of MN risk would aid clinical management and research.nnMETHODS: We analyzed sequenced exomes of healthy UK Biobank (UKB) participants (n = 438,890) in separate derivation and validation cohorts. Genetic mutations, laboratory values, and MN outcomes were used in conditional probability-based recursive partitioning and Cox regression to determine predictors of incident MN. Combined statistical weights defined a clonal hematopoiesis risk score (CHRS). Independent CHIP/CCUS patient cohorts were used to test prognostic capability of the CHRS in the clinical setting.nnRESULTS: Recursive partitioning distinguished CHIP/CCUS cases with 10-year probabilities of MN ranging from 0.0078 - 0.85. Multivariable analysis validated partitioning variables as predictors of MN. Key features, including single  mutations, high risk mutations, ≥ 2 mutations, VAF ≥ 0.2, age ≥ 65 years, CCUS vs CHIP and red blood cell indices, influenced MN risk in variable direction. The CHRS defined low risk (n = 10018, 88.4%), intermediate risk (n = 1196, 10.5%), and high risk (n = 123, 1.1%) groups. In clinical cohorts, most MN events occurred in high risk CHIP/CCUS patients.nnCONCLUSIONS: The CHRS provides simple prognostic framework for CHIP/CCUS, distinguishing a high risk minority from the majority of CHIP/CCUS which has minimal risk for progression to MN.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37188663,
title = {Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy},
author = {Hanna M Ollila and Eilon Sharon and Ling Lin and Nasa Sinnott-Armstrong and Aditya Ambati and Selina M Yogeshwar and Ryan P Hillary and Otto Jolanki and Juliette Faraco and Mali Einen and Guo Luo and Jing Zhang and Fang Han and Han Yan and Xiao Song Dong and Jing Li and Jun Zhang and Seung-Chul Hong and Tae Won Kim and Yves Dauvilliers and Lucie Barateau and Gert Jan Lammers and Rolf Fronczek and Geert Mayer and Joan Santamaria and Isabelle Arnulf and Stine Knudsen-Heier and May Kristin Lyamouri Bredahl and Per Medbøe Thorsby and Giuseppe Plazzi and Fabio Pizza and Monica Moresco and Catherine Crowe and Stephen K Van den Eeden and Michel Lecendreux and Patrice Bourgin and Takashi Kanbayashi and Francisco J Martínez-Orozco and Rosa Peraita-Adrados and Antonio Benetó and Jacques Montplaisir and Alex Desautels and Yu-Shu Huang and  and Poul Jennum and Sona Nevsimalova and David Kemlink and Alex Iranzo and Sebastiaan Overeem and Aleksandra Wierzbicka and Peter Geisler and Karel Sonka and Makoto Honda and Birgit Högl and Ambra Stefani and Fernando Morgadinho Coelho and Vilma Mantovani and Eva Feketeova and Mia Wadelius and Niclas Eriksson and Hans Smedje and Pär Hallberg and Per Egil Hesla and David Rye and Zerrin Pelin and Luigi Ferini-Strambi and Claudio L Bassetti and Johannes Mathis and Ramin Khatami and Adi Aran and Sheela Nampoothiri and Tomas Olsson and Ingrid Kockum and Markku Partinen and Markus Perola and Birgitte R Kornum and Sina Rueger and Juliane Winkelmann and Taku Miyagawa and Hiromi Toyoda and Seik-Soon Khor and Mihoko Shimada and Katsushi Tokunaga and Manuel Rivas and Jonathan K Pritchard and Neil Risch and Zoltan Kutalik and Ruth O'Hara and Joachim Hallmayer and Chun Jimmie Ye and Emmanuel J Mignot},
doi = {10.1038/s41467-023-36120-z},
issn = {2041-1723},
year  = {2023},
date = {2023-05-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {2709},
abstract = {Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37197843,
title = {Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease},
author = {Esra D Gumuser and Art Schuermans and So Mi Jemma Cho and Zachary A Sporn and Md Mesbah Uddin and Kaavya Paruchuri and Tetsushi Nakao and Zhi Yu and Sara Haidermota and Whitney Hornsby and Lachelle D Weeks and Abhishek Niroula and Siddhartha Jaiswal and Peter Libby and Benjamin L Ebert and Alexander G Bick and Pradeep Natarajan and Michael C Honigberg},
doi = {10.1016/j.jacc.2023.03.401},
issn = {1558-3597},
year  = {2023},
date = {2023-05-01},
journal = {J Am Coll Cardiol},
volume = {81},
number = {20},
pages = {1996--2009},
abstract = {BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP)-the age-related clonal expansion of blood stem cells with leukemia-associated mutations-is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear.nnOBJECTIVES: This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD.nnMETHODS: Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression.nnRESULTS: Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001).nnCONCLUSIONS: CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37253881,
title = {A non-coding variant linked to metabolic obesity with normal weight affects actin remodelling in subcutaneous adipocytes},
author = {Viktoria Glunk and Samantha Laber and Nasa Sinnott-Armstrong and Debora R Sobreira and Sophie M Strobel and Thiago M Batista and Phil Kubitz and Bahareh Nemati Moud and Hannah Ebert and Yi Huang and Beate Brandl and Garrett Garbo and Julius Honecker and David R Stirling and Nezar Abdennur and Virtu Calabuig-Navarro and Thomas Skurk and Soeren Ocvirk and Kerstin Stemmer and Beth A Cimini and Anne E Carpenter and Simon N Dankel and Cecilia M Lindgren and Hans Hauner and Marcelo A Nobrega and Melina Claussnitzer},
doi = {10.1038/s42255-023-00807-w},
issn = {2522-5812},
year  = {2023},
date = {2023-05-01},
journal = {Nat Metab},
volume = {5},
number = {5},
pages = {861--879},
abstract = {Recent large-scale genomic association studies found evidence for a genetic link between increased risk of type 2 diabetes and decreased risk for adiposity-related traits, reminiscent of metabolically obese normal weight (MONW) association signatures. However, the target genes and cellular mechanisms driving such MONW associations remain to be identified. Here, we systematically identify the cellular programmes of one of the top-scoring MONW risk loci, the 2q24.3 risk locus, in subcutaneous adipocytes. We identify a causal genetic variant, rs6712203, an intronic single-nucleotide polymorphism in the COBLL1 gene, which changes the conserved transcription factor motif of POU domain, class 2, transcription factor 2, and leads to differential COBLL1 gene expression by altering the enhancer activity at the locus in subcutaneous adipocytes. We then establish the cellular programme under the genetic control of the 2q24.3 MONW risk locus and the effector gene COBLL1, which is characterized by impaired actin cytoskeleton remodelling in differentiating subcutaneous adipocytes and subsequent failure of these cells to accumulate lipids and develop into metabolically active and insulin-sensitive adipocytes. Finally, we show that perturbations of the effector gene Cobll1 in a mouse model result in organismal phenotypes matching the MONW association signature, including decreased subcutaneous body fat mass and body weight along with impaired glucose tolerance. Taken together, our results provide a mechanistic link between the genetic risk for insulin resistance and low adiposity, providing a potential therapeutic hypothesis and a framework for future identification of causal relationships between genome associations and cellular programmes in other disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37068957,
title = {Association of Circulating Metabolites With Racial Disparities in Hypertension and Stroke in the REGARDS Study},
author = {Naruchorn Kijpaisalratana and Zsuzsanna Ament and Amit Patki and Varun M Bhave and Ana-Lucia Garcia-Guarniz and Suzanne E Judd and Mary Cushman and D Leann Long and M Ryan Irvin and W Taylor Kimberly},
doi = {10.1212/WNL.0000000000207264},
issn = {1526-632X},
year  = {2023},
date = {2023-05-01},
journal = {Neurology},
volume = {100},
number = {22},
pages = {e2312--e2320},
abstract = {BACKGROUND AND OBJECTIVES: In the United States, the risk of stroke is greater among Black compared with that among White individuals. However, the reasons for the difference in stroke incidence are not fully elucidated. We aimed to identify metabolites that account for higher prevalent hypertension and incident ischemic stroke among Black adults.nnMETHODS: We used a stroke case cohort nested within the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Targeted metabolomic profiling of 162 plasma metabolites was performed by liquid chromatography-tandem mass spectrometry. We identified metabolites that were associated with prevalent hypertension and incident ischemic stroke and mediated the relationship between hypertension and ischemic stroke by weighted logistic regression, Cox proportional hazard model, and inverse odds ratio weighting mediation analysis.nnRESULTS: Incident ischemic stroke cases adjudicated through April 1, 2019 (n = 1,075) were included in the study. The random cohort sample was derived from the full cohort using stratified sampling (n = 968). Among 162 metabolites, gluconic acid was associated with prevalent hypertension in Black adults (odds ratio [OR] 1.86, 95% CI 1.39-2.47,  = 2.58 × 10) but not in White adults (OR 1.00, 95% CI 0.80-1.24,  = 0.97;  for interaction = 4.57 × 10). Gluconic acid also demonstrated an association with incident ischemic stroke among Black participants (hazard ratio [HR] 1.53, 95% CI 1.28-1.81,  = 1.76 × 10) but not White participants (HR 1.16, 95% CI 1.00-1.34,  = 0.057;  for interaction = 0.019). In mediation analysis, gluconic acid mediated 25.4% (95% CI 4.1%-46.8%,  = 0.02) of the association between prevalent hypertension and incident ischemic stroke among Black individuals. Specific socioeconomic factors were linked to elevated gluconic acid level among Black adults in multivariable analysis, including a Southern dietary pattern (β = 0.18, 95% CI 0.08-0.28,  < 0.001), lower educational attainment (β = 0.45, 95% CI 0.19-0.72,  = 0.001), and a lack of exercise (β = 0.26, 95% CI 0.01-0.51,  = 0.045).nnDISCUSSION: Gluconic acid is associated with prevalent hypertension and incident ischemic stroke and mediates the relationship between hypertension and ischemic stroke in Black but not White adults. Gluconic acid is a biomarker that is associated with social determinants of health including a Southern diet, low educational attainment, and low physical activity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37398055,
title = {A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel regulator of neuronal and synaptic function in the hippocampus},
author = {Maltesh Kambali and Yan Li and Petr Unichenko and Jessica Feria Pliego and Rachita Yadav and Jing Liu and Patrick McGuinness and Johanna G Cobb and Muxiao Wang and Rajasekar Nagarajan and Jinrui Lyu and Vanessa Vongsouthi and Colin J Jackson and Elif Engin and Joseph T Coyle and Jeaweon Shin and Michael E Talkowski and Gregg E Homanics and Vadim Y Bolshakov and Christian Henneberger and Uwe Rudolph},
doi = {10.1101/2023.05.29.542745},
year  = {2023},
date = {2023-05-01},
journal = {bioRxiv},
abstract = {The biological significance of a small supernumerary marker chromosome that results in dosage alterations to chromosome 9p24.1, including triplication of the  gene encoding glycine decarboxylase, in two patients with psychosis is unclear. In an allelic series of copy number variant mouse models, we identify that triplication of  reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) but not in CA1, suppresses long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduces the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displays deficits in prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference. Our results thus provide a link between a genomic copy number variation, biochemical, cellular and behavioral phenotypes, and further demonstrate that GLDC negatively regulates long-term synaptic plasticity at specific hippocampal synapses, possibly contributing to the development of neuropsychiatric disorders.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37207277,
title = {Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia},
author = {Yu-Han H Hsu and Greta Pintacuda and Ruize Liu and Eugeniu Nacu and April Kim and Kalliopi Tsafou and Natalie Petrossian and William Crotty and Jung Min Suh and Jackson Riseman and Jacqueline M Martin and Julia C Biagini and Daya Mena and Joshua K T Ching and Edyta Malolepsza and Taibo Li and Tarjinder Singh and Tian Ge and Shawn B Egri and Benjamin Tanenbaum and Caroline R Stanclift and Annie M Apffel and  and  and Steven A Carr and Monica Schenone and Jake Jaffe and Nadine Fornelos and Hailiang Huang and Kevin C Eggan and Kasper Lage},
doi = {10.1016/j.isci.2023.106701},
issn = {2589-0042},
year  = {2023},
date = {2023-05-01},
journal = {iScience},
volume = {26},
number = {5},
pages = {106701},
abstract = {Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36787958,
title = {Association and Interaction of Genetics and Area-Level Socioeconomic Factors on the Prevalence of Type 2 Diabetes and Obesity},
author = {Sara J Cromer and Chirag M Lakhani and Josep M Mercader and Timothy D Majarian and Philip Schroeder and Joanne B Cole and Jose C Florez and Chirag J Patel and Alisa K Manning and Sherri-Ann M Burnett-Bowie and Jordi Merino and Miriam S Udler},
doi = {10.2337/dc22-1954},
issn = {1935-5548},
year  = {2023},
date = {2023-05-01},
journal = {Diabetes Care},
volume = {46},
number = {5},
pages = {944--952},
abstract = {OBJECTIVE: Quantify the impact of genetic and socioeconomic factors on risk of type 2 diabetes (T2D) and obesity.nnRESEARCH DESIGN AND METHODS: Among participants in the Mass General Brigham Biobank (MGBB) and UK Biobank (UKB), we used logistic regression models to calculate cross-sectional odds of T2D and obesity using 1) polygenic risk scores for T2D and BMI and 2) area-level socioeconomic risk (educational attainment) measures. The primary analysis included 26,737 participants of European genetic ancestry in MGBB with replication in UKB (N = 223,843), as well as in participants of non-European ancestry (MGBB N = 3,468; UKB N = 7,459).nnRESULTS: The area-level socioeconomic measure most strongly associated with both T2D and obesity was percent without a college degree, and associations with disease prevalence were independent of genetic risk (P < 0.001 for each). Moving from lowest to highest quintiles of combined genetic and socioeconomic burden more than tripled T2D (3.1% to 22.2%) and obesity (20.9% to 69.0%) prevalence. Favorable socioeconomic risk was associated with lower disease prevalence, even in those with highest genetic risk (T2D 13.0% vs. 22.2%, obesity 53.6% vs. 69.0% in lowest vs. highest socioeconomic risk quintiles). Additive effects of genetic and socioeconomic factors accounted for 13.2% and 16.7% of T2D and obesity prevalence, respectively, explained by these models. Findings were replicated in independent European and non-European ancestral populations.nnCONCLUSIONS: Genetic and socioeconomic factors significantly interact to increase risk of T2D and obesity. Favorable area-level socioeconomic status was associated with an almost 50% lower T2D prevalence in those with high genetic risk.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36922634,
title = {Down syndrome screening and diagnosis practices in Europe, United States, Australia, and New Zealand from 1990-2021},
author = {Henry C Wilmot and Gert de Graaf and Pieter van Casteren and Frank Buckley and Brian G Skotko},
doi = {10.1038/s41431-023-01330-y},
issn = {1476-5438},
year  = {2023},
date = {2023-05-01},
journal = {Eur J Hum Genet},
volume = {31},
number = {5},
pages = {497--503},
abstract = {Antenatal screening and diagnostic testing for Down syndrome has greatly advanced over the past 30 years. The goal of this manuscript is to provide a review of the availability and accessibility of prenatal services and selective termination policies across Europe, Australia, New Zealand, and the United States for the period 1990-2021. We collected data from academic peer-reviewed journals, governmental documents, not-for-profit organizations, correspondence with experts, and other online sources without language restrictions. Prenatal screening services from 1990-2021 became increasingly available across countries, enabling expectant couples the opportunity to gain more accurate information earlier in the pregnancy before assuming the risk associated with more invasive techniques like CVS or amniocentesis. Many countries also began adopting prenatal screening as a qualification for prenatal diagnosis. As of 2021, at least 76.9% of countries offered full coverage for diagnostic testing for Down syndrome from government funding. Abortion coverage for a Down syndrome diagnosis was covered fully by government funding in 52.4% of countries in 1990, increasing to 73.8% in 2021. Understanding the changing landscape of prenatal services builds the foundation for future investigation into social policies that affect the prevalence of Down syndrome.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37126832,
title = {Distinct Insulin Physiology Trajectories in Euglycemic Pregnancy and Gestational Diabetes Mellitus},
author = {Tanayott Thaweethai and Zainab Soetan and Kaitlyn James and Jose C Florez and Camille E Powe},
doi = {10.2337/dc22-2226},
issn = {1935-5548},
year  = {2023},
date = {2023-05-01},
journal = {Diabetes Care},
abstract = {OBJECTIVE: To evaluate changes in insulin physiology in euglycemic pregnancy and gestational diabetes mellitus (GDM).nnRESEARCH DESIGN AND METHODS: Participants underwent oral glucose tolerance tests at ≤15 weeks' gestation (early pregnancy), 24-32 weeks' gestation (mid-late pregnancy), and 6-24 weeks postpartum. We evaluated longitudinal changes in insulin secretory response (log Stumvoll first-phase estimate) and insulin sensitivity (log Matsuda index) using linear mixed models. We then evaluated participants who met GDM criteria in early pregnancy (early GDM) and mid-late pregnancy (classic GDM) separately from those without GDM. We derived the pregnancy insulin physiology (PIP) index to quantify β-cell compensation for insulin resistance.nnRESULTS: Among 166 participants, 21 had early GDM and 24 developed classic GDM. Insulin sensitivity was reduced slightly in early pregnancy (β = -0.20, P < 0.001) and substantially in mid-late pregnancy (β = -0.47, P < 0.001) compared with postpartum. Insulin secretory response (adjusted for insulin sensitivity) was augmented in early pregnancy (β = 0.16, P < 0.001) and mid-late pregnancy (β = 0.16, P = 0.001) compared with postpartum. Compared with postpartum, the PIP index was augmented in early pregnancy (β = 215, P = 0.04) but not mid-late pregnancy (β = 55, P = 0.64). Early GDM was distinguished by a substantial reduction in early pregnancy insulin sensitivity (β = -0.59, P < 0.001) compared with postpartum. Both early and classic GDM lacked evidence of early pregnancy augmentation of insulin secretory response (adjusted for insulin sensitivity) and the PIP index (P > 0.1 vs. postpartum). Early pregnancy PIP index predicted GDM independent of participant characteristics (area under the curve without PIP index 0.70 [95% CI 0.61-0.79], area under the curve with PIP index 0.87 [95% CI 0.80-0.93]).nnCONCLUSIONS: β-Cell function is enhanced in early pregnancy. Deficient first-trimester β-cell function predicts GDM.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid34915199,
title = {Heart rate response and recovery during exercise predict future delirium risk-A prospective cohort study in middle- to older-aged adults},
author = {Lei Gao and Arlen Gaba and Peng Li and Richa Saxena and Frank A J L Scheer and Oluwaseun Akeju and Martin K Rutter and Kun Hu},
doi = {10.1016/j.jshs.2021.12.002},
issn = {2213-2961},
year  = {2023},
date = {2023-05-01},
journal = {J Sport Health Sci},
volume = {12},
number = {3},
pages = {312--323},
abstract = {BACKGROUND: Delirium is a neurocognitive disorder characterized by an abrupt decline in attention, awareness, and cognition after surgical/illness-induced stressors on the brain. There is now an increasing focus on how cardiovascular health interacts with neurocognitive disorders given their overlapping risk factors and links to subsequent dementia and mortality. One common indicator for cardiovascular health is the heart rate response/recovery (HRR) to exercise, but how this relates to future delirium is unknown.nnMETHODS: Electrocardiogram data were examined in 38,740 middle- to older-aged UK Biobank participants (mean age = 58.1 years, range: 40-72 years; 47.3% males) who completed a standardized submaximal exercise stress test (15-s baseline, 6-min exercise, and 1-min recovery) and required hospitalization during follow-up. An HRR index was derived as the product of the heart rate (HR) responses during exercise (peak/resting HRs) and recovery (peak/recovery HRs) and categorized into low/average/high groups as the bottom quartile/middle 2 quartiles/top quartile, respectively. Associations between 3 HRR groups and new-onset delirium were investigated using Cox proportional hazards models and a 2-year landmark analysis to minimize reverse causation. Sociodemographic factors, lifestyle factors/physical activity, cardiovascular risk, comorbidities, cognition, and maximal workload achieved were included as covariates.nnRESULTS: During a median follow-up period of 11 years, 348 participants (9/1000) newly developed delirium. Compared with the high HRR group (16/1000), the risk for delirium was almost doubled in those with low HRR (hazard ratio = 1.90, 95% confidence interval (95%CI): 1.30-2.79, p = 0.001) and average HRR (hazard ratio = 1.54, 95%CI: 1.07-2.22, p = 0.020)). Low HRR was equivalent to being 6 years older, a current smoker, or ≥3 additional cardiovascular disease risks. Results were robust in sensitivity analysis, but the risk appeared larger in those with better cognition and when only postoperative delirium was considered (n = 147; hazard ratio = 2.66, 95%CI: 1.46-4.85, p = 0.001).nnCONCLUSION: HRR during submaximal exercise is associated with future risk for delirium. Given that HRR is potentially modifiable, it may prove useful for neurological risk stratification alongside traditional cardiovascular risk factors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37226828,
title = {Impact of selection bias on polygenic risk score estimates in healthcare settings},
author = {Younga Heather Lee and Tanayott Thaweethai and Yi-Han Sheu and Yen-Chen Anne Feng and Elizabeth W Karlson and Tian Ge and Peter Kraft and Jordan W Smoller},
doi = {10.1017/S0033291723001186},
issn = {1469-8978},
year  = {2023},
date = {2023-05-01},
journal = {Psychol Med},
pages = {1--11},
abstract = {BACKGROUND: Hospital-based biobanks are being increasingly considered as a resource for translating polygenic risk scores (PRS) into clinical practice. However, since these biobanks originate from patient populations, there is a possibility of bias in polygenic risk estimation due to overrepresentation of patients with higher frequency of healthcare interactions.nnMETHODS: PRS for schizophrenia, bipolar disorder, and depression were calculated using summary statistics from the largest available genomic studies for a sample of 24 153 European ancestry participants in the Mass General Brigham (MGB) Biobank. To correct for selection bias, we fitted logistic regression models with inverse probability (IP) weights, which were estimated using 1839 sociodemographic, clinical, and healthcare utilization features extracted from electronic health records of 1 546 440 non-Hispanic White patients eligible to participate in the Biobank study at their first visit to the MGB-affiliated hospitals.nnRESULTS: Case prevalence of bipolar disorder among participants in the top decile of bipolar disorder PRS was 10.0% (95% CI 8.8-11.2%) in the unweighted analysis but only 6.2% (5.0-7.5%) when selection bias was accounted for using IP weights. Similarly, case prevalence of depression among those in the top decile of depression PRS was reduced from 33.5% (31.7-35.4%) to 28.9% (25.8-31.9%) after IP weighting.nnCONCLUSIONS: Non-random selection of participants into volunteer biobanks may induce clinically relevant selection bias that could impact implementation of PRS in research and clinical settings. As efforts to integrate PRS in medical practice expand, recognition and mitigation of these biases should be considered and may need to be optimized in a context-specific manner.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36477577,
title = {MicroRNAs Associated With Incident Diabetes in the Diabetes Prevention Program},
author = {Elena Flowers and Bradley E Aouizerat and Alka M Kanaya and Jose C Florez and Xingyue Gong and Li Zhang},
doi = {10.1210/clinem/dgac714},
issn = {1945-7197},
year  = {2023},
date = {2023-05-01},
journal = {J Clin Endocrinol Metab},
volume = {108},
number = {6},
pages = {e306--e312},
abstract = {CONTEXT: MicroRNAs (miRs) are short (ie, 18-26 nucleotide) regulatory elements of messenger RNA translation to amino acids.nnOBJECTIVE: The purpose of this study was to assess whether miRs are predictive of incident type 2 diabetes (T2D) in the Diabetes Prevention Program (DPP) trial.nnMETHODS: This was a secondary analysis (n = 1000) of a subset of the DPP cohort that leveraged banked biospecimens to measure miRs. We used random survival forest and Lasso methods to identify the optimal miR predictors and the Cox proportional hazards to model time to T2D overall and within intervention arms.nnRESULTS: We identified 5 miRs (miR-144, miR-186, miR-203a, miR-205, miR-206) that constituted the optimal predictors of incident T2D after adjustment for covariates (hazard ratio [HR] 2.81, 95% CI 2.05, 3.87; P < .001). Predictive risk scores following cross-validation showed the HR for the highest quartile risk group compared with the lowest quartile risk group was 5.91 (95% CI 2.02, 17.3; P < .001). There was significant interaction between the intensive lifestyle (HR 3.60, 95% CI 2.50, 5.18; P < .001) and the metformin (HR 2.72; 95% CI 1.47, 5.00; P = .001) groups compared with placebo. Of the 5 miRs identified, 1 targets a gene with prior known associations with risk for T2D.nnCONCLUSION: We identified 5 miRs that are optimal predictors of incident T2D in the DPP cohort. Future directions include validation of this finding in an independent sample in order to determine whether this risk score may have potential clinical utility for risk stratification of individuals with prediabetes, and functional analysis of the potential genes and pathways targeted by the miRs that were included in the risk score.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36609854,
title = {Response to Letter to the Editor by Palffy and Ghaziuddin},
author = {Stephanie L Santoro and Nicole T Baumer and Michelle Cornacchia and Catherine Franklin and Sarah J Hart and Kelsey Haugen and Margaret A Hojlo and Nora Horick and Priya S Kishnani and Kavita Krell and Andrew McCormick and Anna L Milliken and Nicolas M Oreskovic and Katherine G Pawlowski and Sabrina Sargado and Amy Torres and Diletta Valentini and Kishore Vellody and Brian G Skotko},
doi = {10.1002/ajmg.a.63116},
issn = {1552-4833},
year  = {2023},
date = {2023-05-01},
journal = {Am J Med Genet A},
volume = {191},
number = {5},
pages = {1470--1473},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37205491,
title = {The landscape of tolerated genetic variation in humans and primates},
author = {Hong Gao and Tobias Hamp and Jeffrey Ede and Joshua G Schraiber and Jeremy McRae and Moriel Singer-Berk and Yanshen Yang and Anastasia Dietrich and Petko Fiziev and Lukas Kuderna and Laksshman Sundaram and Yibing Wu and Aashish Adhikari and Yair Field and Chen Chen and Serafim Batzoglou and Francois Aguet and Gabrielle Lemire and Rebecca Reimers and Daniel Balick and Mareike C Janiak and Martin Kuhlwilm and Joseph D Orkin and Shivakumara Manu and Alejandro Valenzuela and Juraj Bergman and Marjolaine Rouselle and Felipe Ennes Silva and Lidia Agueda and Julie Blanc and Marta Gut and Dorien de Vries and Ian Goodhead and R Alan Harris and Muthuswamy Raveendran and Axel Jensen and Idriss S Chuma and Julie Horvath and Christina Hvilsom and David Juan and Peter Frandsen and Fabiano R de Melo and Fabricio Bertuol and Hazel Byrne and Iracilda Sampaio and Izeni Farias and João Valsecchi do Amaral and Mariluce Messias and Maria N F da Silva and Mihir Trivedi and Rogerio Rossi and Tomas Hrbek and Nicole Andriaholinirina and Clément J Rabarivola and Alphonse Zaramody and Clifford J Jolly and Jane Phillips-Conroy and Gregory Wilkerson and Christian Abee and Joe H Simmons and Eduardo Fernandez-Duque and Sree Kanthaswamy and Fekadu Shiferaw and Dongdong Wu and Long Zhou and Yong Shao and Guojie Zhang and Julius D Keyyu and Sascha Knauf and Minh D Le and Esther Lizano and Stefan Merker and Arcadi Navarro and Thomas Batallion and Tilo Nadler and Chiea Chuen Khor and Jessica Lee and Patrick Tan and Weng Khong Lim and Andrew C Kitchener and Dietmar Zinner and Ivo Gut and Amanda Melin and Katerina Guschanski and Mikkel Heide Schierup and Robin M D Beck and Govindhaswamy Umapathy and Christian Roos and Jean P Boubli and Monkol Lek and Shamil Sunyaev and Anne O'Donnell and Heidi Rehm and Jinbo Xu and Jeffrey Rogers and Tomas Marques-Bonet and Kyle Kai-How Farh},
doi = {10.1101/2023.05.01.538953},
year  = {2023},
date = {2023-05-01},
journal = {bioRxiv},
abstract = {Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human. We show that these variants can be inferred to have non-deleterious effects in human based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.nnONE SENTENCE SUMMARY: Deep learning classifier trained on 4.3 million common primate missense variants predicts variant pathogenicity in humans.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37079300,
title = {Overlap of Genetic Loci for Central Serous Chorioretinopathy With Age-Related Macular Degeneration},
author = {Joel T Rämö and Erik Abner and Elon H C van Dijk and Xin Wang and Joost Brinks and Tiit Nikopensius and Margit Nõukas and Heidi Marjonen and Kaisa Silander and Sakari Jukarainen and Tuomo Kiiskinen and Seung Hoan Choi and Risto Kajanne and Juha Mehtonen and Priit Palta and Steven A Lubitz and Kai Kaarniranta and Lucia Sobrin and Mitja Kurki and Suzanne Yzer and Patrick T Ellinor and Tõnu Esko and Mark J Daly and Anneke I den Hollander and Aarno Palotie and Joni A Turunen and Camiel J F Boon and Elizabeth J Rossin and  and },
doi = {10.1001/jamaophthalmol.2023.0706},
issn = {2168-6173},
year  = {2023},
date = {2023-05-01},
journal = {JAMA Ophthalmol},
volume = {141},
number = {5},
pages = {449--457},
abstract = {IMPORTANCE: Central serous chorioretinopathy (CSC) is a serous maculopathy of unknown etiology. Two of 3 previously reported CSC genetic risk loci are also associated with AMD. Improved understanding of CSC genetics may broaden our understanding of this genetic overlap and unveil mechanisms in both diseases.nnOBJECTIVE: To identify novel genetic risk factors for CSC and compare genetic risk factors for CSC and AMD.nnDESIGN, SETTING, AND PARTICIPANTS: Using International Classification of Diseases, Ninth (ICD-9) and Tenth (ICD-10) Revision code-based inclusion and exclusion criteria, patients with CSC and controls were identified in both the FinnGen study and the Estonian Biobank (EstBB). Also included in a meta-analysis were previously reported patients with chronic CSC and controls. Data were analyzed from March 1 to September 31, 2022.nnMAIN OUTCOMES AND MEASURES: Genome-wide association studies (GWASs) were performed in the biobank-based cohorts followed by a meta-analysis of all cohorts. The expression of genes prioritized by the polygenic priority score and nearest-gene methods were assessed in cultured choroidal endothelial cells and public ocular single-cell RNA sequencing data sets. The predictive utility of polygenic scores (PGSs) for CSC and AMD were evaluated in the FinnGen study.nnRESULTS: A total of 1176 patients with CSC and 526 787 controls (312 162 female [59.3%]) were included in this analysis: 552 patients with CSC and 343 461 controls were identified in the FinnGen study, 103 patients with CSC and 178 573 controls were identified in the EstBB, and 521 patients with chronic CSC and 3577 controls were included in a meta-analysis. Two previously reported CSC risk loci were replicated (near CFH and GATA5) and 3 novel loci were identified (near CD34/46, NOTCH4, and PREX1). The CFH and NOTCH4 loci were associated with AMD but in the opposite direction. Prioritized genes showed increased expression in cultured choroidal endothelial cells compared with other genes in the loci (median [IQR] of log 2 [counts per million], 7.3 [0.6] vs 4.7 [3.7]; P = .004) and were differentially expressed in choroidal vascular endothelial cells in single-cell RNA sequencing data (mean [SD] fold change, 2.05 [0.38] compared with other cell types; P < 7.1 × 10-20). A PGS for AMD was predictive of reduced CSC risk (odds ratio, 0.76; 95% CI, 0.70-0.83 per +1 SD in AMD-PGS; P = 7.4 × 10-10). This association may have been mediated by loci containing complement genes.nnCONCLUSIONS AND RELEVANCE: In this 3-cohort genetic association study, 5 genetic risk loci for CSC were identified, highlighting a likely role for genes involved in choroidal vascular function and complement regulation. Results suggest that polygenic AMD risk was associated with reduced risk of CSC and that this genetic overlap was largely due to loci containing complement genes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37188276,
title = {Media use and vaccine resistance},
author = {Jon Green and James N Druckman and Matthew A Baum and Katherine Ognyanova and Matthew D Simonson and Roy H Perlis and David Lazer},
doi = {10.1093/pnasnexus/pgad146},
issn = {2752-6542},
year  = {2023},
date = {2023-05-01},
journal = {PNAS Nexus},
volume = {2},
number = {5},
pages = {pgad146},
abstract = {Public health requires collective action-the public best addresses health crises when individuals engage in prosocial behaviors. Failure to do so can have dire societal and economic consequences. This was made clear by the disjointed, politicized response to COVID-19 in the United States. Perhaps no aspect of the pandemic exemplified this challenge more than the sizeable percentage of individuals who delayed or refused vaccination. While scholars, practitioners, and the government devised a range of communication strategies to persuade people to get vaccinated, much less attention has been paid to where the unvaccinated could be reached. We address this question using multiple waves of a large national survey as well as various secondary data sets. We find that the vaccine resistant seems to predictably obtain information from conservative media outlets (e.g. Fox News) while the vaccinated congregate around more liberal outlets (e.g. MSNBC). We also find consistent evidence that vaccine-resistant individuals often obtain COVID-19 information from various social media, most notably Facebook, rather than traditional media sources. Importantly, such individuals tend to exhibit low institutional trust. While our results do not suggest a failure of sites such as Facebook's institutional COVID-19 efforts, as the counterfactual of no efforts is unknown, they do highlight an opportunity to reach those who are less likely to take vital actions in the service of public health.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37055591,
title = {A lncRNA from an inflammatory bowel disease risk locus maintains intestinal host-commensal homeostasis},
author = {Hongdi Ma and Taidou Hu and Wanyin Tao and Jiyu Tong and Zili Han and Dietmar Herndler-Brandstetter and Zheng Wei and Ruize Liu and Tingyue Zhou and Qiuyuan Liu and Xuemei Xu and Kaiguang Zhang and Rongbin Zhou and Judy H Cho and Hua-Bing Li and Hailiang Huang and Richard A Flavell and Shu Zhu},
doi = {10.1038/s41422-023-00790-7},
issn = {1748-7838},
year  = {2023},
date = {2023-05-01},
journal = {Cell Res},
volume = {33},
number = {5},
pages = {372--388},
abstract = {Inflammatory bowel diseases (IBD) are known to have complex, genetically influenced etiologies, involving dysfunctional interactions between the intestinal immune system and the microbiome. Here, we characterized how the RNA transcript from an IBD-associated long non-coding RNA locus ("CARINH-Colitis Associated IRF1 antisense Regulator of Intestinal Homeostasis") protects against IBD. We show that CARINH and its neighboring gene coding for the transcription factor IRF1 together form a feedforward loop in host myeloid cells. The loop activation is sustained by microbial factors, and functions to maintain the intestinal host-commensal homeostasis via the induction of the anti-inflammatory factor IL-18BP and anti-microbial factors called guanylate-binding proteins (GBPs). Extending these mechanistic insights back to humans, we demonstrate that the function of the CARINH/IRF1 loop is conserved between mice and humans. Genetically, the T allele of rs2188962, the most probable causal variant of IBD within the CARINH locus from the human genetics study, impairs the inducible expression of the CARINH/IRF1 loop and thus increases genetic predisposition to IBD. Our study thus illustrates how an IBD-associated lncRNA maintains intestinal homeostasis and protects the host against colitis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37104749,
title = {CNV-ClinViewer: enhancing the clinical interpretation of large copy-number variants online},
author = {Marie Macnee and Eduardo Pérez-Palma and Tobias Brünger and Chiara Klöckner and Konrad Platzer and Arthur Stefanski and Ludovica Montanucci and Allan Bayat and Maximilian Radtke and Ryan L Collins and Michael Talkowski and Daniel Blankenberg and Rikke S Møller and Johannes R Lemke and Michael Nothnagel and Patrick May and Dennis Lal},
doi = {10.1093/bioinformatics/btad290},
issn = {1367-4811},
year  = {2023},
date = {2023-05-01},
journal = {Bioinformatics},
volume = {39},
number = {5},
abstract = {MOTIVATION: Pathogenic copy-number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts.nnRESULTS: Here, we introduce the CNV-ClinViewer, an open-source web application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface and facilitates semi-automated clinical CNV interpretation following the ACMG guidelines by integrating the ClassifCNV tool. In combination with clinical judgment, the application enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators' patient care and for basic scientists' translational genomic research.nnAVAILABILITY AND IMPLEMENTATION: The web application is freely available at https://cnv-ClinViewer.broadinstitute.org and the open-source code can be found at https://github.com/LalResearchGroup/CNV-clinviewer.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37214979,
title = {Insights from a genome-wide truth set of tandem repeat variation},
author = {Ben Weisburd and Grace Tiao and Heidi L Rehm},
doi = {10.1101/2023.05.05.539588},
year  = {2023},
date = {2023-05-01},
journal = {bioRxiv},
abstract = {Tools for genotyping tandem repeats (TRs) from short read sequencing data have improved significantly over the past decade. Extensive comparisons of these tools to gold standard diagnostic methods like RP-PCR have confirmed their accuracy for tens to hundreds of well-studied loci. However, a scarcity of high-quality orthogonal truth data limited our ability to measure tool accuracy for the millions of other loci throughout the genome. To address this, we developed a TR truth set based on the Synthetic Diploid Benchmark (SynDip). By identifying the subset of insertions and deletions that represent TR expansions or contractions with motifs between 2 and 50 base pairs, we obtained accurate genotypes for 139,795 pure and 6,845 interrupted repeats in a single diploid sample. Our approach did not require running existing genotyping tools on short read or long read sequencing data and provided an alternative, more accurate view of tandem repeat variation. We applied this truth set to compare the strengths and weaknesses of widely-used tools for genotyping TRs, evaluated the completeness of existing genome-wide TR catalogs, and explored the properties of tandem repeat variation throughout the genome. We found that, without filtering, ExpansionHunter had higher accuracy than GangSTR and HipSTR over a wide range of motifs and allele sizes. Also, when errors in allele size occurred, ExpansionHunter tended to overestimate expansion sizes, while GangSTR tended to underestimate them. Additionally, we saw that widely-used TR catalogs miss between 16% and 41% of variant loci in the truth set. These results suggest that genome-wide analyses would benefit from genotyping a larger set of loci as well as further tool development that builds on the strengths of current algorithms. To that end, we developed a new catalog of 2.8 million loci that captures 95% of variant loci in the truth set, and created a modified version of ExpansionHunter that runs 2 to 3x faster than the original while producing the same output.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37398260,
title = {Self-Directed Home-Based Dim-Light Melatonin Onset Collection: The Circadia Pilot Study},
author = {Gregory Bormes and Jessica Love and Akeju Oluwaseun and Jakob Cherry and Lovemore Kunorozva and Salim Qadri and Shadab A Rahman and Brandon Westover and John Winkelman and Jacqueline M Lane},
doi = {10.1101/2023.05.26.23290467},
year  = {2023},
date = {2023-05-01},
journal = {medRxiv},
abstract = {STUDY OBJECTIVES: To test the feasibility of a novel at-home salivary Dim Light Melatonin Onset (DLMO) assessment protocol to measure the endogenous circadian phase of 10 individuals (1 Advanced Sleep-Wake Phase Disorder patient (ASWPD), 4 Delayed Sleep-Wake Phase Disorder patients (DSWPD), and 5 controls).nnMETHODS:  .The study tracked the sleep and activity patterns of 10 individuals over a 5-6 week period using self-reported online sleep diaries and objective actigraphy data. Participants completed two self-directed DLMO assessments, approximately one week apart, adhering to objective compliance measures. Participants completed the study entirely remotely: they completed all sleep diaries and other evaluations online and were mailed a kit with all materials needed to perform the actigraphy and at-home sample collections.nnRESULTS: Salivary DLMO times were calculated for 8/10 participants using the Hockeystick method. DLMO times were on average 3 hours and 18 minutes earlier than self-reported sleep onset times (DSPD: 12:04 AM, controls: 9:55 PM.) Among the 6 participants for whom we calculated two separate DLMO times, DLMOs 1 and 2 were 96% correlated (p<0.0005.).nnCONCLUSIONS: Our results indicate that self-directed, at-home DLMO assessments are feasible and accurate. The current protocol may serve as a framework to reliably assess circadian phase in both clinical and general populations.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37188660,
title = {GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy},
author = {Lisa N Kasiewicz and Souvik Biswas and Aaron Beach and Huilan Ren and Chaitali Dutta and Anne Marie Mazzola and Ellen Rohde and Alexandra Chadwick and Christopher Cheng and Sara P Garcia and Sowmya Iyer and Yuri Matsumoto and Amit V Khera and Kiran Musunuru and Sekar Kathiresan and Padma Malyala and Kallanthottathil G Rajeev and Andrew M Bellinger},
doi = {10.1038/s41467-023-37465-1},
issn = {2041-1723},
year  = {2023},
date = {2023-05-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {2776},
abstract = {Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homozygous familial hypercholesterolemia.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37292770,
title = {Insights into human health from phenome- and genome-wide analyses of UK Biobank retinal optical coherence tomography phenotypes},
author = {Seyedeh Maryam Zekavat and Saman Doroodgar Jorshery and Yusrah Shweikh and Katrin Horn and Franziska G Rauscher and Sayuri Sekimitsu and Satoshi Kayoma and Yixuan Ye and Vineet Raghu and Hongyu Zhao and Marzyeh Ghassemi and Tobias Elze and Ayellet V Segrè and Janey L Wiggs and Markus Scholz and Lucian Del Priore and Jay C Wang and Pradeep Natarajan and Nazlee Zebardast},
doi = {10.1101/2023.05.16.23290063},
year  = {2023},
date = {2023-05-01},
journal = {medRxiv},
abstract = {The human retina is a complex multi-layered tissue which offers a unique window into systemic health and disease. Optical coherence tomography (OCT) is widely used in eye care and allows the non-invasive, rapid capture of retinal measurements in exquisite detail. We conducted genome- and phenome-wide analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed phenome-wide association analyses, associating retinal thicknesses with 1,866 incident ICD-based conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association analyses, identifying inherited genetic markers which influence the retina, and replicated our associations among 6,313 individuals from the LIFE-Adult Study. And lastly, we performed comparative association of phenome- and genome-wide associations to identify putative causal links between systemic conditions, retinal layer thicknesses, and ocular disease. Independent associations with incident mortality were detected for photoreceptor thinning and ganglion cell complex thinning. Significant phenotypic associations were detected between retinal layer thinning and ocular, neuropsychiatric, cardiometabolic and pulmonary conditions. Genome-wide association of retinal layer thicknesses yielded 259 loci. Consistency between epidemiologic and genetic associations suggested putative causal links between thinning of the retinal nerve fiber layer with glaucoma, photoreceptor segment with AMD, as well as poor cardiometabolic and pulmonary function with PS thinning, among other findings. In conclusion, retinal layer thinning predicts risk of future ocular and systemic disease. Furthermore, systemic cardio-metabolic-pulmonary conditions promote retinal thinning. Retinal imaging biomarkers, integrated into electronic health records, may inform risk prediction and potential therapeutic strategies.nnONE SENTENCE SUMMARY: Phenome- and genome-wide associations of retinal OCT images across nearly 50,000 individuals identifies ocular and systemic phenotypes linked to retinal layer thinning, inherited genetic variants linked to retinal layer thickness, and putative causal links between systemic conditions, retinal layer thickness, and ocular disease.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37205493,
title = {Rare penetrant mutations confer severe risk of common diseases},
author = {Petko Fiziev and Jeremy McRae and Jacob C Ulirsch and Jacqueline S Dron and Tobias Hamp and Yanshen Yang and Pierrick Wainschtein and Zijian Ni and Joshua G Schraiber and Hong Gao and Dylan Cable and Yair Field and Francois Aguet and Marc Fasnacht and Ahmed Metwally and Jeffrey Rogers and Tomas Marques-Bonet and Heidi L Rehm and Anne O'Donnell-Luria and Amit V Khera and Kyle Kai-How Farh},
doi = {10.1101/2023.05.01.23289356},
year  = {2023},
date = {2023-05-01},
journal = {medRxiv},
abstract = {We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer ∼10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared to common variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction.nnONE SENTENCE SUMMARY: Rare variant polygenic risk scores identify individuals with outlier phenotypes in common human diseases and complex traits.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37198474,
title = {Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions},
author = {Owen S Skinner and Joan Blanco-Fernández and Russell P Goodman and Akinori Kawakami and Hongying Shen and Lajos V Kemény and Lena Joesch-Cohen and Matthew G Rees and Jennifer A Roth and David E Fisher and Vamsi K Mootha and Alexis A Jourdain},
doi = {10.1038/s42255-023-00774-2},
issn = {2522-5812},
year  = {2023},
date = {2023-05-01},
journal = {Nat Metab},
volume = {5},
number = {5},
pages = {765--776},
abstract = {Glucose is vital for life, serving as both a source of energy and carbon building block for growth. When glucose is limiting, alternative nutrients must be harnessed. To identify mechanisms by which cells can tolerate complete loss of glucose, we performed nutrient-sensitized genome-wide genetic screens and a PRISM growth assay across 482 cancer cell lines. We report that catabolism of uridine from the medium enables the growth of cells in the complete absence of glucose. While previous studies have shown that uridine can be salvaged to support pyrimidine synthesis in the setting of mitochondrial oxidative phosphorylation deficiency, our work demonstrates that the ribose moiety of uridine or RNA can be salvaged to fulfil energy requirements via a pathway based on: (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/UPP2 into uracil and ribose-1-phosphate (R1P), (2) the conversion of uridine-derived R1P into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway and (3) their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis. Capacity for glycolysis from uridine-derived ribose appears widespread, and we confirm its activity in cancer lineages, primary macrophages and mice in vivo. An interesting property of this pathway is that R1P enters downstream of the initial, highly regulated steps of glucose transport and upper glycolysis. We anticipate that 'uridine bypass' of upper glycolysis could be important in the context of disease and even exploited for therapeutic purposes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37220095,
title = {Early Detection of Adrenal Insufficiency: The Impact of Newborn Screening for Adrenoleukodystrophy},
author = {Jonanlis Ramirez Alcantara and Natalie R Grant and Swathi Sethuram and Amanda Nagy and Catherine Becker and Inderneel Sahai and Takara Stanley and Alyssa Halper and Florian S Eichler},
doi = {10.1210/clinem/dgad286},
issn = {1945-7197},
year  = {2023},
date = {2023-05-01},
journal = {J Clin Endocrinol Metab},
abstract = {CONTEXT: Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported.nnOBJECTIVE: To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD.nnDESIGN: We conducted a retrospective medical chart review of pediatric patients with ALD.nnSETTING: All patients were seen in a leukodystrophy clinic in an academic medical center.nnPATIENTS: We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys).nnMAIN OUTCOME MEASURES: We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD.nnRESULTS: Thirty-one (27%) patients were diagnosed with ALD by NBS and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9,12.12] months vs 6.05 [3.74,8.35] years) (p<0.001). When maintenance dose of glucocorticoids were initiated, there were significant differences in ACTH and peak cortisol levels in patients diagnosed by NBS and outside the newborn period.nnCONCLUSIONS: Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37225367,
title = {Increased Risk of Thoracic Aortic Aneurysms With JAK2 V617F},
author = {Tetsushi Nakao and Zhi Yu and Caitlyn Vlasschaert and Md Mesbah Uddin and Mark E Lindsay and Patrick T Ellinor and Benjamin L Ebert and Alexander G Bick and James P Pirruccello and Pradeep Natarajan},
doi = {10.1016/j.jacc.2023.03.413},
issn = {1558-3597},
year  = {2023},
date = {2023-05-01},
journal = {J Am Coll Cardiol},
volume = {81},
number = {21},
pages = {2128--2130},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36655393,
title = {Designing an international survey for organisations serving people with Down syndrome},
author = {Daniel J Kats and Brian G Skotko and Gert de Graaf and Ellen Skladzien and Brian Takashi Hooper and Rose Mordi and Tetiana Mykhailenko and Frank Buckley and Vasiliki Patsiogiannis and Kavita Krell and Kelsey Haugen and Karen Donelan},
doi = {10.1111/jar.13071},
issn = {1468-3148},
year  = {2023},
date = {2023-05-01},
journal = {J Appl Res Intellect Disabil},
volume = {36},
number = {3},
pages = {497--506},
abstract = {BACKGROUND: Down syndrome is the most common liveborn genetic condition. However, there are no surveys measuring societal services and supports for people with Down syndrome. We developed a questionnaire so that initiatives could be targeted towards countries most in need of assistance.nnMETHOD: We formed a geographically diverse group of physicians, family members of people with Down syndrome, and members of Down syndrome not-for-profit organisations to create a survey of societal services and supports. We used a modified Delphi method and disseminated the survey to Down syndrome non-profit organisations worldwide.nnRESULTS: Our survey consists of 61 items categorised within five domains: Education, Community Inclusion, Independence, Healthcare, and Social and Policy Issues.nnCONCLUSIONS: We developed a survey to measure societal services and supports available to people with Down syndrome as perceived by organisational leaders. Our methods might serve as a blueprint for other populations of people with intellectual and developmental disabilities.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37293016,
title = {Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators},
author = {Anastasia Schultz and Shun-Yun Cheng and Emily Kirchner and Stephanann Costello and Heini Miettinen and Marta Chaverra and Colin King and Lynn George and Xin Zhao and Jana Narasimhan and Marla Weetall and Susan Slaugenhaupt and Elisabetta Morini and Claudio Punzo and Frances Lefcort},
doi = {10.1101/2023.05.22.541535},
year  = {2023},
date = {2023-05-01},
journal = {bioRxiv},
abstract = {Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (  ) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently, patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical data foundation for translation to FD patients.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37186683,
title = {Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease},
author = {Yiyi Zhang and Jacqueline S Dron and Brandon K Bellows and Amit V Khera and Junxiu Liu and Pallavi P Balte and Elizabeth C Oelsner and Sami Samir Amr and Matthew S Lebo and Anna Nagy and Gina M Peloso and Pradeep Natarajan and Jerome I Rotter and Cristen Willer and Eric Boerwinkle and Christie M Ballantyne and Pamela L Lutsey and Myriam Fornage and Donald M Lloyd-Jones and Lifang Hou and Bruce M Psaty and Joshua C Bis and James S Floyd and Ramachandran S Vasan and Nancy L Heard-Costa and April P Carson and Michael E Hall and Stephen S Rich and Xiuqing Guo and Dhruv S Kazi and Sarah D de Ferranti and Andrew E Moran},
doi = {10.1161/CIRCULATIONAHA.123.064168},
issn = {1524-4539},
year  = {2023},
date = {2023-05-01},
journal = {Circulation},
volume = {147},
number = {20},
pages = {1556--1559},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36865155,
title = {Genetic variation supports a causal role for valproate in prevention of ischemic stroke},
author = {Ernst Mayerhofer and Livia Parodi and Kaavya Narasimhalu and Stefan Wolking and Andreas Harloff and Marios K Georgakis and Jonathan Rosand and Christopher D Anderson},
doi = {10.1101/2023.02.14.23285856},
year  = {2023},
date = {2023-05-01},
journal = {medRxiv},
abstract = {Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. To overcome this limitation, we applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. Among 2,150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12-year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 μg/ml per one SD, 95% CI [3.45, 8.11]). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (HR per one SD 0.73, [0.58, 0.91]) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p-trend=0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per one SD 0.53, [0.32, 0.86]) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs. 13/71, 18.3%, p-trend=0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p=0.61), suggesting minimal pleiotropy. In an independent cohort of 1,241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per one SD 0.77, 95% CI: [0.61, 0.97]). These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37217678,
title = {Genetic predisposition to macronutrient preference and workplace food choices},
author = {Jordi Merino and Hassan S Dashti and Douglas E Levy and Magdalena Del Rocío Sevilla-González and Marie-France Hivert and Bianca C Porneala and Richa Saxena and Anne N Thorndike},
doi = {10.1038/s41380-023-02107-x},
issn = {1476-5578},
year  = {2023},
date = {2023-05-01},
journal = {Mol Psychiatry},
abstract = {Prior research identified genetic variants influencing macronutrient preference, but whether genetic differences underlying nutrient preference affect long-term food choices is unknown. Here we examined the associations of polygenic scores for carbohydrate, fat, and protein preference with 12 months' workplace food purchases among 397 hospital employees from the ChooseWell 365 study. Food purchases were obtained retrospectively from the hospital's cafeteria sales data for the 12 months before participants were enrolled in the ChooseWell 365 study. Traffic light labels, visible to employees when making purchases, measured the quality of workplace purchases. During the 12-month study period, there were 215,692 cafeteria purchases. Each SD increase in the polygenic score for carbohydrate preference was associated with 2.3 additional purchases/month (95%CI, 0.2 to 4.3; p = 0.03) and a higher number of green-labeled purchases (β = 1.9, 95%CI, 0.5-3.3; p = 0.01). These associations were consistent in subgroup and sensitivity analyses accounting for additional sources of bias. There was no evidence of associations between fat and protein polygenic scores and cafeteria purchases. Findings from this study suggest that genetic differences in carbohydrate preference could influence long-term workplace food purchases and may inform follow-up experiments to enhance our understanding of the molecular mechanisms underlying food choice behavior.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37377635,
title = {Exploring the link between Gilbert's syndrome and atherosclerotic cardiovascular disease: insights from a subpopulation-based analysis of over one million individuals},
author = {Uri Kartoun and Akl C Fahed and Shinwan Kany and Pulkit Singh and Shaan Khurshid and Aniruddh P Patel and Puneet Batra and Anthony Philippakis and Amit V Khera and Steven A Lubitz and Patrick T Ellinor and Vibha Anand and Kenney Ng},
doi = {10.1093/ehjopen/oead059},
issn = {2752-4191},
year  = {2023},
date = {2023-05-01},
journal = {Eur Heart J Open},
volume = {3},
number = {3},
pages = {oead059},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36745605,
title = {Polygenic Scores Help Reduce Racial Disparities in Predictive Accuracy of Automated Type 1 Diabetes Classification Algorithms},
author = {Aaron J Deutsch and Lauren Stalbow and Timothy D Majarian and Josep M Mercader and Alisa K Manning and Jose C Florez and Ruth J F Loos and Miriam S Udler},
doi = {10.2337/dc22-1833},
issn = {1935-5548},
year  = {2023},
date = {2023-04-01},
journal = {Diabetes Care},
volume = {46},
number = {4},
pages = {794--800},
abstract = {OBJECTIVE: Automated algorithms to identify individuals with type 1 diabetes using electronic health records are increasingly used in biomedical research. It is not known whether the accuracy of these algorithms differs by self-reported race. We investigated whether polygenic scores improve identification of individuals with type 1 diabetes.nnRESEARCH DESIGN AND METHODS: We investigated two large hospital-based biobanks (Mass General Brigham [MGB] and BioMe) and identified individuals with type 1 diabetes using an established automated algorithm. We performed medical record reviews to validate the diagnosis of type 1 diabetes. We implemented two published polygenic scores for type 1 diabetes (developed in individuals of European or African ancestry). We assessed the classification algorithm before and after incorporating polygenic scores.nnRESULTS: The automated algorithm was more likely to incorrectly assign a diagnosis of type 1 diabetes in self-reported non-White individuals than in self-reported White individuals (odds ratio 3.45; 95% CI 1.54-7.69; P = 0.0026). After incorporating polygenic scores into the MGB Biobank, the positive predictive value of the type 1 diabetes algorithm increased from 70 to 97% for self-reported White individuals (meaning that 97% of those predicted to have type 1 diabetes indeed had type 1 diabetes) and from 53 to 100% for self-reported non-White individuals. Similar results were found in BioMe.nnCONCLUSIONS: Automated phenotyping algorithms may exacerbate health disparities because of an increased risk of misclassification of individuals from underrepresented populations. Polygenic scores may be used to improve the performance of phenotyping algorithms and potentially reduce this disparity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37043557,
title = {A prolyl oligopeptidase inhibitor reduces tau pathology in cellular models and in mice with tauopathy},
author = {Tony S Eteläinen and M Catarina Silva and Johanna K Uhari-Väänänen and Francesca De Lorenzo and Maria H Jäntti and Hengjing Cui and Marta Chavero-Pieres and Tommi Kilpeläinen and Christina Mechtler and Reinis Svarcbahs and Erin Seppälä and Juha R Savinainen and Elena Puris and Gert Fricker and Mikko Gynther and Ulrika H Julku and Henri J Huttunen and Stephen J Haggarty and Timo T Myöhänen},
doi = {10.1126/scitranslmed.abq2915},
issn = {1946-6242},
year  = {2023},
date = {2023-04-01},
journal = {Sci Transl Med},
volume = {15},
number = {691},
pages = {eabq2915},
abstract = {Tauopathies are neurodegenerative diseases that are characterized by accumulation of hyperphosphorylated tau protein, higher-order aggregates, and tau filaments. Protein phosphatase 2A (PP2A) is a major tau dephosphorylating phosphatase, and a decrease in its activity has been demonstrated in tauopathies, including Alzheimer's disease. Prolyl oligopeptidase is a serine protease that is associated with neurodegeneration, and its inhibition normalizes PP2A activity without toxicity under pathological conditions. Here, we assessed whether prolyl oligopeptidase inhibition could protect against tau-mediated toxicity in cellular models in vitro and in the PS19 transgenic mouse model of tauopathy carrying the human tau-P301S mutation. We show that inhibition of prolyl oligopeptidase with the inhibitor KYP-2047 reduced tau aggregation in tau-transfected HEK-293 cells and N2A cells as well as in human iPSC-derived neurons carrying either the P301L or tau-A152T mutation. Treatment with KYP-2047 resulted in increased PP2A activity and activation of autophagic flux in HEK-293 cells and N2A cells and in patient-derived iNeurons, as indicated by changes in autophagosome and autophagy receptor markers; this contributed to clearance of insoluble tau. Furthermore, treatment of PS19 transgenic mice for 1 month with KYP-2047 reduced tau burden in the brain and cerebrospinal fluid and slowed cognitive decline according to several behavioral tests. In addition, a reduction in an oxidative stress marker was seen in mouse brains after KYP-2047 treatment. This study suggests that inhibition of prolyl oligopeptidase could help to ameliorate tau-dependent neurodegeneration.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37046084,
title = {Clonal haematopoiesis and risk of chronic liver disease},
author = {Waihay J Wong and Connor Emdin and Alexander G Bick and Seyedeh M Zekavat and Abhishek Niroula and James P Pirruccello and Laura Dichtel and Gabriel Griffin and Md Mesbah Uddin and Christopher J Gibson and Veronica Kovalcik and Amy E Lin and Marie E McConkey and Amelie Vromman and Rob S Sellar and Peter G Kim and Mridul Agrawal and Joshua Weinstock and Michelle T Long and Bing Yu and Rajarshi Banerjee and Rowan C Nicholls and Andrea Dennis and Matt Kelly and Po-Ru Loh and Steve McCarroll and Eric Boerwinkle and Ramachandran S Vasan and Siddhartha Jaiswal and Andrew D Johnson and Raymond T Chung and Kathleen Corey and Daniel Levy and Christie Ballantyne and  and Benjamin L Ebert and Pradeep Natarajan},
doi = {10.1038/s41586-023-05857-4},
issn = {1476-4687},
year  = {2023},
date = {2023-04-01},
journal = {Nature},
volume = {616},
number = {7958},
pages = {747--754},
abstract = {Chronic liver disease is a major public health burden worldwide. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37081156,
title = {Topologically associating domain boundaries are required for normal genome function},
author = {Sudha Rajderkar and Iros Barozzi and Yiwen Zhu and Rong Hu and Yanxiao Zhang and Bin Li and Ana Alcaina Caro and Yoko Fukuda-Yuzawa and Guy Kelman and Adyam Akeza and Matthew J Blow and Quan Pham and Anne N Harrington and Janeth Godoy and Eman M Meky and Kianna von Maydell and Riana D Hunter and Jennifer A Akiyama and Catherine S Novak and Ingrid Plajzer-Frick and Veena Afzal and Stella Tran and Javier Lopez-Rios and Michael E Talkowski and K C Kent Lloyd and Bing Ren and Diane E Dickel and Axel Visel and Len A Pennacchio},
doi = {10.1038/s42003-023-04819-w},
issn = {2399-3642},
year  = {2023},
date = {2023-04-01},
journal = {Commun Biol},
volume = {6},
number = {1},
pages = {435},
abstract = {Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes, but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11-80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37131648,
title = {Research Letter: Application of GPT-4 to select next-step antidepressant treatment in major depression},
author = {Roy H Perlis},
doi = {10.1101/2023.04.14.23288595},
year  = {2023},
date = {2023-04-01},
journal = {medRxiv},
abstract = {INTRODUCTION: Large language models perform well on a range of academic tasks including medical examinations. The performance of this class of models in psychopharmacology has not been explored.nnMETHOD: Chat GPT-plus, implementing the GPT-4 large language model, was presented with each of 10 previously-studied antidepressant prescribing vignettes in randomized order, with results regenerated 5 times to evaluate stability of responses. Results were compared to expert consensus.nnRESULTS: At least one of the optimal medication choices was included among the best choices in 38/50 (76%) vignettes: 5/5 for 7 vignettes, 3/5 for 1, and 0/5 for 2. At least one of the poor choice or contraindicated medications was included among the choices considered optimal or good in 24/50 (48%) of vignettes. The model provided as rationale for treatment selection multiple heuristics including avoiding prior unsuccessful medications, avoiding adverse effects based on comorbidities, and generalizing within medication class.nnCONCLUSION: The model appeared to identify and apply a number of heuristics commonly applied in psychopharmacologic clinical practice. However, the inclusion of less optimal recommendations indicates that large language models may pose a substantial risk if routinely applied to guide psychopharmacologic treatment without further monitoring.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36463093,
title = {Recommendations to improve the patient experience and avoid bias when prenatal screening/testing},
author = {Stephanie Meredith and Scotti Brackett and Keith M Diaz and Kathleen G Freeman and Erin Huggins and Hadia Khan and Mark W Leach and Mitchell Levitz and Marsha Michie and Janet Onufer and Brian G Skotko and Leah Smith and A Nicole White and Tracy Waller and Kara Ayers and },
doi = {10.1016/j.dhjo.2022.101401},
issn = {1876-7583},
year  = {2023},
date = {2023-04-01},
journal = {Disabil Health J},
volume = {16},
number = {2},
pages = {101401},
abstract = {While prenatal screening and testing have expanded substantially over the past decade and provide access to more genetic information, expectant parents are more likely to describe the diagnosis experience as negative than positive. In addition, the conversations that take place during these experiences sometimes reflect unconscious bias against people with disabilities. Consequently, an interdisciplinary committee of experts, including people with disabilities, family members, disability organization leaders, healthcare and genetics professionals, and bioethicists, reviewed selected published and gray literature comparing the current state of the administration of prenatal testing to the ideal state. Subsequently, the interdisciplinary team created recommendations for clinicians, public health agencies, medical organizations, federal agencies, and other stakeholders involved with administering prenatal screening and testing to create better patient experiences; conduct training for healthcare professionals; create, enforce, and fund policies and guidelines; and engage in more robust data collection and research efforts.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36621880,
title = {Returning integrated genomic risk and clinical recommendations: The eMERGE study},
author = {Jodell E Linder and Aimee Allworth and Harris T Bland and Pedro J Caraballo and Rex L Chisholm and Ellen Wright Clayton and David R Crosslin and Ozan Dikilitas and Alanna DiVietro and Edward D Esplin and Sophie Forman and Robert R Freimuth and Adam S Gordon and Richard Green and Maegan V Harden and Ingrid A Holm and Gail P Jarvik and Elizabeth W Karlson and Sofia Labrecque and Niall J Lennon and Nita A Limdi and Kathleen F Mittendorf and Shawn N Murphy and Lori Orlando and Cynthia A Prows and Luke V Rasmussen and Laura Rasmussen-Torvik and Robb Rowley and Konrad Teodor Sawicki and Tara Schmidlen and Shannon Terek and David Veenstra and Digna R Velez Edwards and Devin Absher and Noura S Abul-Husn and Jorge Alsip and Hana Bangash and Mark Beasley and Jennifer E Below and Eta S Berner and James Booth and Wendy K Chung and James J Cimino and John Connolly and Patrick Davis and Beth Devine and Stephanie M Fullerton and Candace Guiducci and Melissa L Habrat and Heather Hain and Hakon Hakonarson and Margaret Harr and Eden Haverfield and Valentina Hernandez and Christin Hoell and Martha Horike-Pyne and George Hripcsak and Marguerite R Irvin and Christopher Kachulis and Dean Karavite and Eimear E Kenny and Atlas Khan and Krzysztof Kiryluk and Bruce Korf and Leah Kottyan and Iftikhar J Kullo and Katie Larkin and Cong Liu and Edyta Malolepsza and Teri A Manolio and Thomas May and Elizabeth M McNally and Frank Mentch and Alexandra Miller and Sean D Mooney and Priyanka Murali and Brenda Mutai and Naveen Muthu and Bahram Namjou and Emma F Perez and Megan J Puckelwartz and Tejinder Rakhra-Burris and Dan M Roden and Elisabeth A Rosenthal and Seyedmohammad Saadatagah and Maya Sabatello and Dan J Schaid and Baergen Schultz and Lynn Seabolt and Gabriel Q Shaibi and Richard R Sharp and Brian Shirts and Maureen E Smith and Jordan W Smoller and Rene Sterling and Sabrina A Suckiel and Jeritt Thayer and Hemant K Tiwari and Susan B Trinidad and Theresa Walunas and Wei-Qi Wei and Quinn S Wells and Chunhua Weng and Georgia L Wiesner and Ken Wiley and  and Josh F Peterson},
doi = {10.1016/j.gim.2023.100006},
issn = {1530-0366},
year  = {2023},
date = {2023-04-01},
journal = {Genet Med},
volume = {25},
number = {4},
pages = {100006},
abstract = {PURPOSE: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.nnMETHODS: To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report and will assess uptake of care recommendations after return of results.nnRESULTS: GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.nnCONCLUSION: Return of a novel report for communicating monogenic, polygenic, and family history-based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37043533,
title = {A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes},
author = {Ping-Chieh Pao and Jinsoo Seo and Audrey Lee and Oleg Kritskiy and Debasis Patnaik and Jay Penney and Ravikiran M Raju and Ute Geigenmuller and M Catarina Silva and Diane E Lucente and James F Gusella and Bradford C Dickerson and Anjanet Loon and Margaret X Yu and Michael Bula and Melody Yu and Stephen J Haggarty and Li-Huei Tsai},
doi = {10.1073/pnas.2217864120},
issn = {1091-6490},
year  = {2023},
date = {2023-04-01},
journal = {Proc Natl Acad Sci U S A},
volume = {120},
number = {16},
pages = {e2217864120},
abstract = {Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This deleterious effect is mediated by pathological cleavage of the Cdk5 activator p35 into the truncated product p25, leading to prolonged Cdk5 activation and altered substrate specificity. Elevated p25 levels have been reported in humans and rodents with neurodegeneration, and the benefit of genetically blocking p25 production has been demonstrated previously in rodent and human neurodegenerative models. Here, we report a 12-amino-acid-long peptide fragment derived from Cdk5 (Cdk5i) that is considerably smaller than existing peptide inhibitors of Cdk5 (P5 and CIP) but shows high binding affinity toward the Cdk5/p25 complex, disrupts the interaction of Cdk5 with p25, and lowers Cdk5/p25 kinase activity. When tagged with a fluorophore (FITC) and the cell-penetrating transactivator of transcription (TAT) sequence, the Cdk5i-FT peptide exhibits cell- and brain-penetrant properties and confers protection against neurodegenerative phenotypes associated with Cdk5 hyperactivity in cell and mouse models of neurodegeneration, highlighting Cdk5i's therapeutic potential.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37043637,
title = {Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland},
author = {Caroline F Wright and Patrick Campbell and Ruth Y Eberhardt and Stuart Aitken and Daniel Perrett and Simon Brent and Petr Danecek and Eugene J Gardner and V Kartik Chundru and Sarah J Lindsay and Katrina Andrews and Juliet Hampstead and Joanna Kaplanis and Kaitlin E Samocha and Anna Middleton and Julia Foreman and Rachel J Hobson and Michael J Parker and Hilary C Martin and David R FitzPatrick and Matthew E Hurles and Helen V Firth and },
doi = {10.1056/NEJMoa2209046},
issn = {1533-4406},
year  = {2023},
date = {2023-04-01},
journal = {N Engl J Med},
volume = {388},
number = {17},
pages = {1559--1571},
abstract = {BACKGROUND: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits.nnMETHODS: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis.nnRESULTS: A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78).nnCONCLUSIONS: Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37046083,
title = {Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis},
author = {Joshua S Weinstock and Jayakrishnan Gopakumar and Bala Bharathi Burugula and Md Mesbah Uddin and Nikolaus Jahn and Julia A Belk and Hind Bouzid and Bence Daniel and Zhuang Miao and Nghi Ly and Taralynn M Mack and Sofia E Luna and Katherine P Prothro and Shaneice R Mitchell and Cecelia A Laurie and Jai G Broome and Kent D Taylor and Xiuqing Guo and Moritz F Sinner and Aenne S von Falkenhausen and Stefan Kääb and Alan R Shuldiner and Jeffrey R O'Connell and Joshua P Lewis and Eric Boerwinkle and Kathleen C Barnes and Nathalie Chami and Eimear E Kenny and Ruth J F Loos and Myriam Fornage and Lifang Hou and Donald M Lloyd-Jones and Susan Redline and Brian E Cade and Bruce M Psaty and Joshua C Bis and Jennifer A Brody and Edwin K Silverman and Jeong H Yun and Dandi Qiao and Nicholette D Palmer and Barry I Freedman and Donald W Bowden and Michael H Cho and Dawn L DeMeo and Ramachandran S Vasan and Lisa R Yanek and Lewis C Becker and Sharon L R Kardia and Patricia A Peyser and Jiang He and Michiel Rienstra and Pim Van der Harst and Robert Kaplan and Susan R Heckbert and Nicholas L Smith and Kerri L Wiggins and Donna K Arnett and Marguerite R Irvin and Hemant Tiwari and Michael J Cutler and Stacey Knight and J Brent Muhlestein and Adolfo Correa and Laura M Raffield and Yan Gao and Mariza de Andrade and Jerome I Rotter and Stephen S Rich and Russell P Tracy and Barbara A Konkle and Jill M Johnsen and Marsha M Wheeler and J Gustav Smith and Olle Melander and Peter M Nilsson and Brian S Custer and Ravindranath Duggirala and Joanne E Curran and John Blangero and Stephen McGarvey and L Keoki Williams and Shujie Xiao and Mao Yang and C Charles Gu and Yii-Der Ida Chen and Wen-Jane Lee and Gregory M Marcus and John P Kane and Clive R Pullinger and M Benjamin Shoemaker and Dawood Darbar and Dan M Roden and Christine Albert and Charles Kooperberg and Ying Zhou and JoAnn E Manson and Pinkal Desai and Andrew D Johnson and Rasika A Mathias and  and Thomas W Blackwell and Goncalo R Abecasis and Albert V Smith and Hyun M Kang and Ansuman T Satpathy and Pradeep Natarajan and Jacob O Kitzman and Eric A Whitsel and Alexander P Reiner and Alexander G Bick and Siddhartha Jaiswal},
doi = {10.1038/s41586-023-05806-1},
issn = {1476-4687},
year  = {2023},
date = {2023-04-01},
journal = {Nature},
volume = {616},
number = {7958},
pages = {755--763},
abstract = {Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36718090,
title = {SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia},
author = {Siddharth Srivastava and Hagar Mor Shaked and Kenneth Gable and Sita D Gupta and Xueyang Pan and Niranjanakumari Somashekarappa and Gongshe Han and Payam Mohassel and Marc Gotkine and Elizabeth Doney and Paula Goldenberg and Queenie K G Tan and Yi Gong and Benjamin Kleinstiver and Brian Wishart and Heidi Cope and Claudia Brito Pires and Hannah Stutzman and Rebecca C Spillmann and  and Reza Sadjadi and Orly Elpeleg and Chia-Hsueh Lee and Hugo J Bellen and Simon Edvardson and Florian Eichler and Teresa M Dunn},
doi = {10.1093/brain/awac460},
issn = {1460-2156},
year  = {2023},
date = {2023-04-01},
journal = {Brain},
volume = {146},
number = {4},
pages = {1420--1435},
abstract = {Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia. The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila. Our results showed that two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals. The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila. These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37027164,
title = {Group Home Staff Experiences With Work and Health in the COVID-19 Pandemic in Massachusetts},
author = {Karen Donelan and Jessica Wolfe and Anna Wilson and Carie Michael and Cindy Chau and David Krane and Paula Silverman and Jessica E Becker and David Cheng and Elizabeth Cella and Bruce Bird and Julie H Levison and Brian G Skotko and Stephen J Bartels},
doi = {10.1001/jamahealthforum.2023.0445},
issn = {2689-0186},
year  = {2023},
date = {2023-04-01},
journal = {JAMA Health Forum},
volume = {4},
number = {4},
pages = {e230445},
abstract = {IMPORTANCE: Direct reports of the experiences of staff working in group homes for people with serious mental illness (SMI) and/or intellectual or developmental disabilities (ID/DD) are rarely reported. Hearing from workers about their experiences in the COVID-19 pandemic may inform future workforce and public policy.nnOBJECTIVE: To gather baseline data on worker experience with the perceived effects of COVID-19 on health and work in the pandemic prior to initiating an intervention to mitigate the spread of COVID-19 and to measure differences in worker experience by gender, race, ethnicity, education, and resident population served (persons with SMI and/or IDD/DD).nnDESIGN, SETTING, AND PARTICIPANTS: This mixed-mode, cross-sectional survey study was conducted using online then paper-based self-administration from May to September 2021 at the end of the first year of the pandemic. Staff working in 415 group homes that provided care within 6 Massachusetts organizations serving adults aged 18 years or older with SMI and/or ID/DD were surveyed. The eligible survey population included a census of staff who were currently employed in participating group homes during the study period. A total of 1468 staff completed or partially completed surveys. The overall survey response rate was 44% (range by organization, 20% to 52%).nnMAIN OUTCOMES AND MEASURES: Self-reported experiential outcomes were measured in work, health, and vaccine completion. Bivariate and multivariate analyses explore experiences by gender, race, ethnicity, education, trust in experts and employers, and population served.nnRESULTS: The study population included 1468 group home staff (864 [58.9%] women; 818 [55.7%] non-Hispanic Black; 98 [6.7%] Hispanic or Latino). A total of 331 (22.5%) group home staff members reported very serious perceived effects on health; 438 (29.8%) reported very serious perceived effects on mental health; 471 (32.1%) reported very serious perceived effects on health of family and friends; and 414 reported very serious perceived effects (28.2%) on access to health services, with statistically significant differences observed by race and ethnicity. Vaccine acceptance was higher among persons with higher educational attainment and trust in scientific expertise and lower among persons who self-reported as Black or Hispanic/Latino. A total of 392 (26.7%) respondents reported needing support for health needs, and 290 (19.8%) respondents reported needing support for loneliness or isolation.nnCONCLUSIONS AND RELEVANCE: In this survey study, approximately one-third of group home workers reported serious personal health and access to health care barriers during the first year of the COVID-19 pandemic in Massachusetts. Addressing unmet health needs and access to health and mental health services, including inequities and disparities by race, ethnicity, and education, should benefit staff health and safety, as well as that of the individuals with disabilities who rely on them for support and care.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36707304,
title = {Reply},
author = {Seyedeh Maryam Zekavat and Sayuri Sekimitsu and Saman Doroodgar Jorshery and Pradeep Natarajan and Elizabeth J Rossin and Lucian Del Priore and Nazlee Zebardast and Jay C Wang},
doi = {10.1016/j.ophtha.2022.12.003},
issn = {1549-4713},
year  = {2023},
date = {2023-04-01},
journal = {Ophthalmology},
volume = {130},
number = {4},
pages = {e15--e16},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36891905,
title = {Genetically Proxied CRP (C-Reactive Protein) Levels and Lobar Intracerebral Hemorrhage Risk},
author = {Evangelos Pavlos Myserlis and Christopher D Anderson and Marios K Georgakis},
doi = {10.1161/STROKEAHA.122.041889},
issn = {1524-4628},
year  = {2023},
date = {2023-04-01},
journal = {Stroke},
volume = {54},
number = {4},
pages = {e130--e132},
abstract = {BACKGROUND: Recent evidence suggests that higher CRP (C-reactive protein) levels are associated with lower risk of Alzheimer disease, speculating that CRP might be involved in Aβ clearance mechanisms. Testing this hypothesis, we explored whether genetically proxied CRP levels are also associated with lobar intracerebral hemorrhage (ICH), commonly caused by cerebral amyloid angiopathy.nnMETHODS: We used 4 genetic variants within the  gene that explain up to 64% of the variance of circulating CRP levels and explored in 2-sample Mendelian randomization analyses associations with risk of any, lobar, and deep ICH (1545 cases and 1481 controls).nnRESULTS: Higher genetically proxied CRP levels were associated with lower odds of lobar ICH (odds ratio per SD increment in CRP, 0.45 [95% CI, 0.25-0.73]) but not deep ICH (odds ratio, 0.72 [95% CI, 0.45-1.14]). There was evidence of colocalization (posterior probability of association, 72.4%) in the signals for CRP and lobar ICH.nnCONCLUSIONS: Our results provide supportive evidence that high CRP levels may have a protective role in amyloid-related pathology.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37080587,
title = {Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis},
author = {Marzieh Akhlaghpour and Talin Haritunians and Shyam K More and Lisa S Thomas and Dalton T Stamps and Shishir Dube and Dalin Li and Shaohong Yang and Carol J Landers and Emebet Mengesha and Hussein Hamade and Ramachandran Murali and Alka A Potdar and Andrea J Wolf and Gregory J Botwin and Michelle Khrom and  and Ashwin N Ananthakrishnan and William A Faubion and Bana Jabri and Sergio A Lira and Rodney D Newberry and Robert S Sandler and R Balfour Sartor and Ramnik J Xavier and Steven R Brant and Judy H Cho and Richard H Duerr and Mark G Lazarev and John D Rioux and L Philip Schumm and Mark S Silverberg and Karen Zaghiyan and Phillip Fleshner and Gil Y Melmed and Eric A Vasiliauskas and Christina Ha and Shervin Rabizadeh and Gaurav Syal and Nirupama N Bonthala and David A Ziring and Stephan R Targan and Millie D Long and Dermot P B McGovern and Kathrin S Michelsen},
doi = {10.1136/gutjnl-2023-329689},
issn = {1468-3288},
year  = {2023},
date = {2023-04-01},
journal = {Gut},
abstract = {OBJECTIVE: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in  ().nnDESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from  risk, or protective CD or healthy subjects was assessed by flow cytometry.nnRESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in , in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum.nnCONCLUSION: pCD-associated rs4151651 in  is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36343677,
title = {Genetically Predicted Serum Vitamin C Levels and Cutaneous Squamous Cell Carcinoma Risk},
author = {Yuhree Kim and Jie Yin and Stephen Le Breton and Eric Jorgenson and Hailiang Huang and Hélène Choquet and Maryam M Asgari},
doi = {10.1016/j.jid.2022.10.006},
issn = {1523-1747},
year  = {2023},
date = {2023-04-01},
journal = {J Invest Dermatol},
volume = {143},
number = {4},
pages = {664--667},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36963395,
title = {The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits},
author = {Maria C Costanzo and Marcin von Grotthuss and Jeffrey Massung and Dongkeun Jang and Lizz Caulkins and Ryan Koesterer and Clint Gilbert and Ryan P Welch and Parul Kudtarkar and Quy Hoang and Andrew P Boughton and Preeti Singh and Ying Sun and Marc Duby and Annie Moriondo and Trang Nguyen and Patrick Smadbeck and Benjamin R Alexander and MacKenzie Brandes and Mary Carmichael and Peter Dornbos and Todd Green and Kenneth C Huellas-Bruskiewicz and Yue Ji and Alexandria Kluge and Aoife C McMahon and Josep M Mercader and Oliver Ruebenacker and Sebanti Sengupta and Dylan Spalding and Daniel Taliun and  and Philip Smith and Melissa K Thomas and Beena Akolkar and M Julia Brosnan and Andriy Cherkas and Audrey Y Chu and Eric B Fauman and Caroline S Fox and Tania Nayak Kamphaus and Melissa R Miller and Lynette Nguyen and Afshin Parsa and Dermot F Reilly and Hartmut Ruetten and David Wholley and Norann A Zaghloul and Gonçalo R Abecasis and David Altshuler and Thomas M Keane and Mark I McCarthy and Kyle J Gaulton and Jose C Florez and Michael Boehnke and Noël P Burtt and Jason Flannick},
doi = {10.1016/j.cmet.2023.03.001},
issn = {1932-7420},
year  = {2023},
date = {2023-04-01},
journal = {Cell Metab},
volume = {35},
number = {4},
pages = {695--710.e6},
abstract = {Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37090938,
title = {Transcriptome and Genome Analysis Uncovers a  Structural Variant: A Case Report},
author = {Chiara Folland and Vijay Ganesh and Ben Weisburd and Catriona McLean and Andrew J Kornberg and Anne O'Donnell-Luria and Heidi L Rehm and Igor Stevanovski and Sanjog R Chintalaphani and Paul Kennedy and Ira W Deveson and Gianina Ravenscroft},
doi = {10.1212/NXG.0000000000200064},
issn = {2376-7839},
year  = {2023},
date = {2023-04-01},
journal = {Neurol Genet},
volume = {9},
number = {2},
pages = {e200064},
abstract = {OBJECTIVE: Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the dystrophin gene (). Hypermethylated CGG expansions within  5' UTR are associated with an intellectual development disorder. Here, we demonstrate the diagnostic utility of genomic short-read sequencing (SRS) and transcriptome sequencing to identify a novel  structural variant (SV) and a  CGG expansion in a patient with DMD for whom conventional diagnostic testing failed to yield a genetic diagnosis.nnMETHODS: We performed genomic SRS, skeletal muscle transcriptome sequencing, and targeted programmable long-read sequencing (LRS).nnRESULTS: The proband had a typical DMD clinical presentation, autism spectrum disorder (ASD), and dystrophinopathy on muscle biopsy. Transcriptome analysis identified 6 aberrantly expressed genes;  and  were the strongest underexpression and overexpression outliers, respectively. Genomic SRS identified a 216 kb paracentric inversion (NC_000023.11: g.33162217-33378800) overlapping 2  promoters. ExpansionHunter indicated an expansion of 109 CGG repeats within the 5' UTR of . Targeted genomic LRS confirmed the SV and genotyped the  repeat expansion as 270 CGG repeats.nnDISCUSSION: Here, transcriptome data heavily guided genomic analysis to resolve a complex  inversion and a  repeat expansion. Longitudinal follow-up will be important for clarifying the clinical significance of the  genotype.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37081778,
title = {Health Surveillance in a Down Syndrome Specialty Clinic: Implementation of Electronic Health Record Integrations During the Coronavirus Disease 2019 Pandemic},
author = {Stephanie L Santoro and Yamini J Howe and Kavita Krell and Brian G Skotko and John Patrick T Co},
doi = {10.1016/j.jpeds.2022.10.021},
issn = {1097-6833},
year  = {2023},
date = {2023-04-01},
journal = {J Pediatr},
volume = {255},
pages = {58--64.e6},
abstract = {OBJECTIVE: To address gaps in routine recommended care for children with Down syndrome, through quality improvement during the coronavirus disease 2019 (COVID-19) pandemic.nnSTUDY DESIGN: A retrospective chart review of patients with Down syndrome was conducted. Records of visits to the Massachusetts General Hospital Down Syndrome Program were assessed for adherence to 5 components of the 2011 American Academy of Pediatrics (AAP) Clinical Report, "Health Supervision for Children with Down Syndrome." The impact of 2 major changes was analyzed using statistical process control charts: a planned intervention of integrations to the electronic health record for routine health maintenance with age-based logic based on a diagnosis of Down syndrome, created and implemented in July 2020; and a natural disruption in care due to the COVID-19 pandemic, starting in March 2020.nnRESULTS: From December 2018 to March 2022, 433 patients with Down syndrome had 940 visits. During the COVID-19 pandemic, adherence to the audiology component decreased (from 58% to 45%, P < .001); composite adherence decreased but later improved. Ophthalmology evaluation remained stable. Improvement in adherence to 3 components (thyroid-stimulating hormone, hemoglobin, sleep study ever) in July 2020 coincided with electronic health record integrations. Total adherence to the 5 AAP guideline components was greater for follow-up visits compared with new patient visits (69% and 61%, respectively; P < .01).nnCONCLUSIONS: The COVID-19 pandemic influenced adherence to components of the AAP Health supervision for children with Down syndrome, but improvements in adherence coincided with implementation of our intervention and reopening after the COVID-19 pandemic.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36937991,
title = {Genomic analysis of lean individuals with NAFLD identifies monogenic disorders in a prospective cohort study},
author = {Melanie Zheng and Daniel Q Huang and Chigoziri Konkwo and Saaket Agrawal and Amit V Khera and Rohit Loomba and Sílvia Vilarinho and Veeral Ajmera},
doi = {10.1016/j.jhepr.2023.100692},
issn = {2589-5559},
year  = {2023},
date = {2023-04-01},
journal = {JHEP Rep},
volume = {5},
number = {4},
pages = {100692},
abstract = {BACKGROUND & AIMS: Lean patients with non-alcoholic fatty liver disease (NAFLD) represent 10-20% of the affected population and may have heterogeneous drivers of disease. We have recently proposed the evaluation of patients with lean NAFLD without visceral adiposity for rare monogenic drivers of disease. Here, we aimed to validate this framework in a well-characterised cohort of patients with biopsy-proven NAFLD by performing whole exome sequencing.nnMETHODS: This prospective study included 124 patients with biopsy-proven NAFLD and paired liver biopsies who underwent standardised research visits including advanced magnetic resonance imaging (MRI) assessment of liver fat and stiffness.nnRESULTS: Six patients with lean NAFLD were identified and underwent whole exome sequencing. Two lean patients (33%) were identified to have monogenic disorders. The lean patients with monogenic disorders had similar age, and anthropometric and MRI characteristics to lean patients without a monogenic disorder. Patient 1 harbours a rare homozygous pathogenic mutation in  (aldolase B) and was diagnosed with hereditary fructose intolerance. Patient 2 harbours a rare heterozygous mutation in apolipoprotein B (). The pathogenicity of this  variant (p.Val1856CysfsTer2) was further validated in the UK Biobank and associated with lower circulating APOB levels (beta = -0.51 g/L, 95% CI -0.65 to -0.36 g/L,  = 1.4 × 10) and higher liver fat on MRI (beta = +10.4%, 95% CI 4.3-16.5%,  = 8.8 × 10). Hence, patient 2 was diagnosed with heterozygous familial hypobetalipoproteinaemia.nnCONCLUSIONS: In this cohort of well-characterised patients with lean NAFLD without visceral adiposity, 33% (2/6) had rare monogenic drivers of disease, highlighting the importance of genomic analysis in this NAFLD subtype.nnIMPACT AND IMPLICATIONS: Although most people with non-alcoholic fatty liver disease (NAFLD) are overweight or obese, a subset are lean and may have unique genetic mutations that cause their fatty liver disease. We show that 33% of study participants with NAFLD who were lean harboured unique mutations that cause their fatty liver, and that these mutations had effects beyond the liver. This study demonstrates the value of genetic assessment of NAFLD in lean individuals to identify distinct subtypes of disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36799223,
title = {A Genomic Risk Score Identifies Individuals at High Risk for Intracerebral Hemorrhage},
author = {Evangelos Pavlos Myserlis and Marios K Georgakis and Stacie L Demel and Padmini Sekar and Jaeyoon Chung and Rainer Malik and Hyacinth I Hyacinth and Mary E Comeau and Guido J Falcone and Carl D Langefeld and Jonathan Rosand and Daniel Woo and Christopher D Anderson},
doi = {10.1161/STROKEAHA.122.041701},
issn = {1524-4628},
year  = {2023},
date = {2023-04-01},
journal = {Stroke},
volume = {54},
number = {4},
pages = {973--982},
abstract = {BACKGROUND: Intracerebral hemorrhage (ICH) has an estimated heritability of 29%. We developed a genomic risk score for ICH and determined its predictive power in comparison to standard clinical risk factors.nnMETHODS: We combined genome-wide association data from individuals of European ancestry for ICH and related traits in a meta-genomic risk score ([metaGRS]; 2.6 million variants). We tested associations with ICH and its predictive performance in addition to clinical risk factors in a held-out validation dataset (842 cases and 796 controls). We tested associations with risk of incident ICH in the population-based UK Biobank cohort (486 784 individuals, 1526 events, median follow-up 11.3 years).nnRESULTS: One SD increment in the metaGRS was significantly associated with 31% higher odds for ICH (95% CI, 1.16-1.48) in age-, sex- and clinical risk factor-adjusted models. The metaGRS identified individuals with almost 5-fold higher odds for ICH in the top score percentile (odds ratio, 4.83 [95% CI, 1.56-21.2]). Predictive models for ICH incorporating the metaGRS in addition to clinical predictors showed superior performance compared to the clinical risk factors alone (c-index, 0.695 versus 0.686). The metaGRS showed similar associations for lobar and nonlobar ICH, independent of the known  risk locus for lobar ICH. In the UK Biobank, the metaGRS was associated with higher risk of incident ICH (hazard ratio, 1.15 [95% CI, 1.09-1.21]). The associations were significant within both a relatively high-risk population of antithrombotic medications users, as well as among a relatively low-risk population with a good control of vascular risk factors and no use of anticoagulants.nnCONCLUSIONS: We developed and validated a genomic risk score that predicts lifetime risk of ICH beyond established clinical risk factors among individuals of European ancestry. Whether implementation of the score in risk prognostication models for high-risk populations, such as patients under antithrombotic treatment, could improve clinical decision making should be explored in future studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37098414,
title = {Review of databases for experimentally validated human microRNA-mRNA interactions},
author = {Dorian Kariuki and Kesava Asam and Bradley E Aouizerat and Kimberly A Lewis and Jose C Florez and Elena Flowers},
doi = {10.1093/database/baad014},
issn = {1758-0463},
year  = {2023},
date = {2023-04-01},
journal = {Database (Oxford)},
volume = {2023},
abstract = {MicroRNAs (miRs) may contribute to disease etiology by influencing gene expression. Numerous databases are available for miR target prediction and validation, but their functionality is varied, and outputs are not standardized. The purpose of this review is to identify and describe databases for cataloging validated miR targets. Using Tools4miRs and PubMed, we identified databases with experimentally validated targets, human data, and a focus on miR-messenger RNA (mRNA) interactions. Data were extracted about the number of times each database was cited, the number of miRs, the target genes, the interactions per database, experimental methodology and key features of each database. The search yielded 10 databases, which in order of most cited to least were: miRTarBase, starBase/The Encyclopedia of RNA Interactomes, DIANA-TarBase, miRWalk, miRecords, miRGator, miRSystem, miRGate, miRSel and targetHub. Findings from this review suggest that the information presented within miR target validation databases can be enhanced by adding features such as flexibility in performing queries in multiple ways, downloadable data, ongoing updates and integrating tools for further miR-mRNA target interaction analysis. This review is designed to aid researchers, especially those new to miR bioinformatics tools, in database selection and to offer considerations for future development and upkeep of validation tools. Database URL http://mirtarbase.cuhk.edu.cn/.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37162872,
title = {Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's disease},
author = {Doo Eun Choi and Jun Wan Shin and Sophia Zeng and Eun Pyo Hong and Jae-Hyun Jang and Jacob M Loupe and Vanessa C Wheeler and Hannah E Stutzman and Benjamin P Kleinstiver and Jong-Min Lee},
doi = {10.1101/2023.04.28.538700},
year  = {2023},
date = {2023-04-01},
journal = {bioRxiv},
abstract = {An expanded CAG repeat in the huntingtin gene (  ) causes Huntington's disease (HD). Since the length of uninterrupted CAG repeat, not polyglutamine, determines the age-at-onset in HD, base editing strategies to convert CAG to CAA are anticipated to delay onset by shortening the uninterrupted CAG repeat. Here, we developed base editing strategies to convert CAG in the repeat to CAA and determined their molecular outcomes and effects on relevant disease phenotypes. Base editing strategies employing combinations of cytosine base editors and gRNAs efficiently converted CAG to CAA at various sites in the CAG repeat without generating significant indels, off-target edits, or transcriptome alterations, demonstrating their feasibility and specificity. Candidate BE strategies converted CAG to CAA on both expanded and non-expanded CAG repeats without altering  mRNA and protein levels. In addition, somatic CAG repeat expansion, which is the major disease driver in HD, was significantly decreased by a candidate BE strategy treatment in HD knock-in mice carrying canonical CAG repeats. Notably, CAG repeat expansion was abolished entirely in HD knock-in mice carrying CAA-interrupted repeats, supporting the therapeutic potential of CAG-to-CAA conversion base editing strategies in HD and potentially other repeat expansion disorders.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37066341,
title = {Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci},
author = {Nurlan Kerimov and Ralf Tambets and James D Hayhurst and Ida Rahu and Peep Kolberg and Uku Raudvere and Ivan Kuzmin and Anshika Chowdhary and Andreas Vija and Hans J Teras and Masahiro Kanai and Jacob Ulirsch and Mina Ryten and John Hardy and Sebastian Guelfi and Daniah Trabzuni and Sarah Kim-Hellmuth and Will Rayner and Hilary Finucane and Hedi Peterson and Abayomi Mosaku and Helen Parkinson and Kaur Alasoo},
doi = {10.1101/2023.04.06.535816},
year  = {2023},
date = {2023-04-01},
journal = {bioRxiv},
abstract = {Splicing quantitative trait loci (QTLs) have been implicated as a common mechanism underlying complex trait associations. However, utilising splicing QTLs in target discovery and prioritisation has been challenging due to extensive data normalisation which often renders the direction of the genetic effect as well as its magnitude difficult to interpret. This is further complicated by the fact that strong expression QTLs often manifest as weak splicing QTLs and vice versa, making it difficult to uniquely identify the underlying molecular mechanism at each locus. We find that these ambiguities can be mitigated by visualising the association between the genotype and average RNA sequencing read coverage in the region. Here, we generate these QTL coverage plots for 1.7 million molecular QTL associations in the eQTL Catalogue identified with five quantification methods. We illustrate the utility of these QTL coverage plots by performing colocalisation between vitamin D levels in the UK Biobank and all molecular QTLs in the eQTL Catalogue. We find that while visually confirmed splicing QTLs explain just 6/53 of the colocalising signals, they are significantly less pleiotropic than eQTLs and identify a prioritised causal gene in 4/6 cases. All our association summary statistics and QTL coverage plots are freely available at https://www.ebi.ac.uk/eqtl/ .},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37131632,
title = {Systematic review of precision subclassification of type 2 diabetes},
author = {Shivani Misra and Robert Wagner and Bige Ozkan and Martin Schön and Magdalena Sevilla-Gonzalez and Katsiaryna Prystupa and Caroline C Wang and Raymond J Kreienkamp and Sara J Cromer and Mary R Rooney and Daisy Duan and Anne Cathrine Baun Thuesen and Amelia S Wallace and Aaron Leong and Aaron J Deutsch and Mette K Andersen and Liana K Billings and Robert H Eckel and Wayne Huey-Herng Sheu and Torben Hansen and Norbert Stefan and Mark O Goodarzi and Debashree Ray and Elizabeth Selvin and Jose C Florez and  and James B Meigs and Miriam S Udler},
doi = {10.1101/2023.04.19.23288577},
year  = {2023},
date = {2023-04-01},
journal = {medRxiv},
abstract = {Heterogeneity in type 2 diabetes presentation, progression and treatment has the potential for precision medicine interventions that can enhance care and outcomes for affected individuals. We undertook a systematic review to ascertain whether strategies to subclassify type 2 diabetes are associated with improved clinical outcomes, show reproducibility and have high quality evidence. We reviewed publications that deployed 'simple subclassification' using clinical features, biomarkers, imaging or other routinely available parameters or 'complex subclassification' approaches that used machine learning and/or genomic data. We found that simple stratification approaches, for example, stratification based on age, body mass index or lipid profiles, had been widely used, but no strategy had been replicated and many lacked association with meaningful outcomes. Complex stratification using clustering of simple clinical data with and without genetic data did show reproducible subtypes of diabetes that had been associated with outcomes such as cardiovascular disease and/or mortality. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into meaningful groups. More studies are needed to test these subclassifications in more diverse ancestries and prove that they are amenable to interventions.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37126548,
title = {The genetic determinants of recurrent somatic mutations in 43,693 blood genomes},
author = {Joshua S Weinstock and Cecelia A Laurie and Jai G Broome and Kent D Taylor and Xiuqing Guo and Alan R Shuldiner and Jeffrey R O'Connell and Joshua P Lewis and Eric Boerwinkle and Kathleen C Barnes and Nathalie Chami and Eimear E Kenny and Ruth J F Loos and Myriam Fornage and Susan Redline and Brian E Cade and Frank D Gilliland and Zhanghua Chen and W James Gauderman and Rajesh Kumar and Leslie Grammer and Robert P Schleimer and Bruce M Psaty and Joshua C Bis and Jennifer A Brody and Edwin K Silverman and Jeong H Yun and Dandi Qiao and Scott T Weiss and Jessica Lasky-Su and Dawn L DeMeo and Nicholette D Palmer and Barry I Freedman and Donald W Bowden and Michael H Cho and Ramachandran S Vasan and Andrew D Johnson and Lisa R Yanek and Lewis C Becker and Sharon Kardia and Jiang He and Robert Kaplan and Susan R Heckbert and Nicholas L Smith and Kerri L Wiggins and Donna K Arnett and Marguerite R Irvin and Hemant Tiwari and Adolfo Correa and Laura M Raffield and Yan Gao and Mariza de Andrade and Jerome I Rotter and Stephen S Rich and Ani W Manichaikul and Barbara A Konkle and Jill M Johnsen and Marsha M Wheeler and Brian S Custer and Ravindranath Duggirala and Joanne E Curran and John Blangero and Hongsheng Gui and Shujie Xiao and L Keoki Williams and Deborah A Meyers and Xingnan Li and Victor Ortega and Stephen McGarvey and C Charles Gu and Yii-Der Ida Chen and Wen-Jane Lee and M Benjamin Shoemaker and Dawood Darbar and Dan Roden and Christine Albert and Charles Kooperberg and Pinkal Desai and Thomas W Blackwell and Goncalo R Abecasis and Albert V Smith and Hyun M Kang and Rasika Mathias and Pradeep Natarajan and Siddhartha Jaiswal and Alexander P Reiner and Alexander G Bick and },
doi = {10.1126/sciadv.abm4945},
issn = {2375-2548},
year  = {2023},
date = {2023-04-01},
journal = {Sci Adv},
volume = {9},
number = {17},
pages = {eabm4945},
abstract = {Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37066232,
title = {Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms},
author = {Angharad M Roberts and Marina T DiStefano and Erin Rooney Riggs and Katherine S Josephs and Fowzan S Alkuraya and Joanna Amberger and Mutaz Amin and Jonathan S Berg and Fiona Cunningham and Karen Eilbeck and Helen V Firth and Julia Foreman and Ada Hamosh and Eleanor Hay and Sarah Leigh and Christa L Martin and Ellen M McDonagh and Daniel Perrett and Erin M Ramos and Peter N Robinson and Ana Rath and David van Sant and Zornitza Stark and Nicola Whiffin and Heidi L Rehm and James S Ware},
doi = {10.1101/2023.03.30.23287948},
year  = {2023},
date = {2023-04-01},
journal = {medRxiv},
abstract = {PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework.nnMETHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition (GenCC) members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated.nnRESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both sequence ontology (SO) and human phenotype ontology (HPO) ontologies. GenCC member groups intend to use or map to these terms in their respective resources.nnCONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36873096,
title = {Low and differential polygenic score generalizability among African populations due largely to genetic diversity},
author = {Lerato Majara and Allan Kalungi and Nastassja Koen and Kristin Tsuo and Ying Wang and Rahul Gupta and Lethukuthula L Nkambule and Heather Zar and Dan J Stein and Eugene Kinyanda and Elizabeth G Atkinson and Alicia R Martin},
doi = {10.1016/j.xhgg.2023.100184},
issn = {2666-2477},
year  = {2023},
date = {2023-04-01},
journal = {HGG Adv},
volume = {4},
number = {2},
pages = {100184},
abstract = {African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across groups. Differences in African ancestries contribute more to variability in PRS accuracy than other large cohort differences considered between individuals in the United Kingdom versus Uganda. We computed PRS in African ancestry populations using existing European-only versus ancestrally diverse genetic studies; the increased diversity produced the largest accuracy gains for hemoglobin concentration and white blood cell count, reflecting large-effect ancestry-enriched variants in genes known to influence sickle cell anemia and the allergic response, respectively. Differences in PRS accuracy across African ancestries originating from diverse regions are as large as across out-of-Africa continental ancestries, requiring commensurate nuance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37080976,
title = {Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients},
author = {Yiming Wu and Kyle Gettler and Meltem Ece Kars and Mamta Giri and Dalin Li and Cigdem Sevim Bayrak and Peng Zhang and Aayushee Jain and Patrick Maffucci and Ksenija Sabic and Tielman Van Vleck and Girish Nadkarni and Lee A Denson and Harry Ostrer and Adam P Levine and Elena R Schiff and Anthony W Segal and Subra Kugathasan and Peter D Stenson and David N Cooper and L Philip Schumm and Scott Snapper and Mark J Daly and Talin Haritunians and Richard H Duerr and Mark S Silverberg and John D Rioux and Steven R Brant and Dermot P B McGovern and Judy H Cho and Yuval Itan},
doi = {10.1038/s41467-023-37849-3},
issn = {2041-1723},
year  = {2023},
date = {2023-04-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {2256},
abstract = {Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36634217,
title = {Examining the shared etiology of psychopathology with genome-wide association studies},
author = {Travis T Mallard and Andrew D Grotzinger and Jordan W Smoller},
doi = {10.1152/physrev.00016.2022},
issn = {1522-1210},
year  = {2023},
date = {2023-04-01},
journal = {Physiol Rev},
volume = {103},
number = {2},
pages = {1645--1665},
abstract = {Genome-wide association studies (GWASs) have ushered in a new era of reproducible discovery in psychiatric genetics. The field has now identified hundreds of common genetic variants that are associated with mental disorders, and many of them influence more than one disorder. By advancing the understanding of causal biology underlying psychopathology, GWAS results are poised to inform the development of novel therapeutics, stratification of at-risk patients, and perhaps even the revision of top-down classification systems in psychiatry. Here, we provide a concise review of GWAS findings with an emphasis on findings that have elucidated the shared genetic etiology of psychopathology, summarizing insights at three levels of analysis: ) genome-wide architecture; ) networks, pathways, and gene sets; and ) individual variants/genes. Three themes emerge from these efforts. First, all psychiatric phenotypes are heritable, highly polygenic, and influenced by many pleiotropic variants with incomplete penetrance. Second, GWAS results highlight the broad etiological roles of neuronal biology, system-wide effects over localized effects, and early neurodevelopment as a critical period. Third, many loci that are robustly associated with multiple forms of psychopathology harbor genes that are involved in synaptic structure and function. Finally, we conclude our review by discussing the implications that GWAS results hold for the field of psychiatry, as well as expected challenges and future directions in the next stage of psychiatric genetics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37045567,
title = {Cohort profile: SUPER-Finland - the Finnish study for hereditary mechanisms of psychotic disorders},
author = {Markku Lähteenvuo and Ari Ahola-Olli and Kimmo Suokas and Minna Holm and Zuzanna Misiewicz and Tuomas Jukuri and Teemu Männynsalo and Asko Wegelius and Willehard Haaki and Risto Kajanne and Aija Kyttälä and Annamari Tuulio-Henriksson and Kaisla Lahdensuo and Katja Häkkinen and Jarmo Hietala and Tiina Paunio and Jussi Niemi-Pynttäri and Tuula Kieseppä and Juha Veijola and Jouko Lönnqvist and Erkki Isometsä and Olli Kampman and Jari Tiihonen and Steven Hyman and Benjamin Neale and Mark Daly and Jaana Suvisaari and Aarno Palotie},
doi = {10.1136/bmjopen-2022-070710},
issn = {2044-6055},
year  = {2023},
date = {2023-04-01},
journal = {BMJ Open},
volume = {13},
number = {4},
pages = {e070710},
abstract = {PURPOSE: SUPER-Finland is a large Finnish collection of psychosis cases. This cohort also represents the Finnish contribution to the Stanley Global Neuropsychiatric Genetics Initiative, which seeks to diversify genetic sample collection to include Asian, Latin American and African populations in addition to known population isolates, such as Finland.nnPARTICIPANTS: 10 474 individuals aged 18 years or older were recruited throughout the country. The subjects have been genotyped with a genome-wide genotyping chip and exome sequenced. A subset of 897 individuals selected from known population sub-isolates were selected for whole-genome sequencing. Recruitment was done between November 2015 and December 2018.nnFINDINGS TO DATE: 5757 (55.2%) had a diagnosis of schizophrenia, 944 (9.1%) schizoaffective disorder, 1612 (15.5%) type I or type II bipolar disorder, 532 (5.1 %) psychotic depression, 1047 (10.0%) other psychosis and for 530 (5.1%) self-reported psychosis at recruitment could not be confirmed from register data. Mean duration of schizophrenia was 22.0 years at the time of the recruitment. By the end of the year 2018, 204 of the recruited individuals had died. The most common cause of death was cardiovascular disease (n=61) followed by neoplasms (n=40). Ten subjects had psychiatric morbidity as the primary cause of death.nnFUTURE PLANS: Compare the effects of common variants, rare variants and copy number variations (CNVs) on severity of psychotic illness. In addition, we aim to track longitudinal course of illness based on nation-wide register data to estimate how phenotypic and genetic differences alter it.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37011137,
title = {Genetic and Clinical Factors Underlying a Self-Reported Family History of Heart Disease},
author = {Amanda Jowell and Romit Bhattacharya and Christopher Marnell and Megan Wong and Sara Haidermota and Mark Trinder and Akl C Fahed and Gina M Peloso and Michael C Honigberg and Pradeep Natarajan},
doi = {10.1093/eurjpc/zwad096},
issn = {2047-4881},
year  = {2023},
date = {2023-04-01},
journal = {Eur J Prev Cardiol},
abstract = {AIM: To estimate how much information conveyed by self reported family history of heart disease (FHHD) is already explained by clinical and genetic risk factors.nnMETHODS: Cross-sectional analysis of UK Biobank participants without preexisting coronary artery disease using a multivariable model with self-reported FHHD as the outcome. Clinical (diabetes, hypertension, smoking, apolipoprotein B-to-apolipoprotein AI ratio, waist-to-hip ratio, high sensitivity C-reactive protein, lipoprotein(a), triglycerides) and genetic risk factors (polygenic risk score for coronary artery disease [PRSCAD], heterozygous familial hypercholesterolemia [HeFH]) were exposures. Models were adjusted for age, sex, and cholesterol-lowering medication use. Multiple logistic regression models were fitted to associate FHHD with risk factors, with continuous variables treated as quintiles. Population attributable risks (PAR) were subsequently calculated from the resultant odds ratios.nnRESULTS: Among 166,714 individuals, 72,052 (43.2%) participants reported a FHHD. In a multivariable model, genetic risk factors PRSCAD (OR 1.30, CI 1.27-1.33), and HeFH (OR 1.31, 1.11-1.54) were most strongly associated with FHHD. Clinical risk factors followed: hypertension (OR 1.18, CI 1.15-1.21), Lp(a) (OR 1.17, CI 1.14-1.20), apolipoprotein B-to-apolipoprotein AI ratio, (OR 1.13, 95% CI 1.10-1.16) and triglycerides (OR 1.07, CI 1.04-1.10). For the PAR analyses: 21.9% (CI 18.19-25.63) of the risk of reporting a FHHD is attributed to clinical factors, 22.2% (CI% 20.44-23.88) is attributed to genetic factors, and 36.0% (CI 33.31-38.68) is attributed to genetic and clinical factors combined.nnCONCLUSIONS: A combined model of clinical and genetic risk factors explains only 36% of the likelihood of FHHD, implying additional value in the family history.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36799992,
title = {Variants in DTNA cause a mild, dominantly inherited muscular dystrophy},
author = {Andres Nascimento and Christine C Bruels and Sandra Donkervoort and A Reghan Foley and Anna Codina and Jose C Milisenda and Elicia A Estrella and Chengcheng Li and Jordi Pijuan and Isabelle Draper and Ying Hu and Seth A Stafki and Lynn S Pais and Vijay S Ganesh and Anne O'Donnell-Luria and Safoora B Syeda and Laura Carrera-García and Jessica Expósito-Escudero and Delia Yubero and Loreto Martorell and Iago Pinal-Fernandez and Hart G W Lidov and Andrew L Mammen and Josep M Grau-Junyent and Carlos Ortez and Francesc Palau and Partha S Ghosh and Basil T Darras and Cristina Jou and Louis M Kunkel and Janet Hoenicka and Carsten G Bönnemann and Peter B Kang and Daniel Natera-de Benito},
doi = {10.1007/s00401-023-02551-7},
issn = {1432-0533},
year  = {2023},
date = {2023-04-01},
journal = {Acta Neuropathol},
volume = {145},
number = {4},
pages = {479--496},
abstract = {DTNA encodes α-dystrobrevin, a component of the macromolecular dystrophin-glycoprotein complex (DGC) that binds to dystrophin/utrophin and α-syntrophin. Mice lacking α-dystrobrevin have a muscular dystrophy phenotype, but variants in DTNA have not previously been associated with human skeletal muscle disease. We present 12 individuals from four unrelated families with two different monoallelic DTNA variants affecting the coiled-coil domain of α-dystrobrevin. The five affected individuals from family A harbor a c.1585G > A; p.Glu529Lys variant, while the recurrent c.1567_1587del; p.Gln523_Glu529del DTNA variant was identified in the other three families (family B: four affected individuals, family C: one affected individual, and family D: two affected individuals). Myalgia and exercise intolerance, with variable ages of onset, were reported in 10 of 12 affected individuals. Proximal lower limb weakness with onset in the first decade of life was noted in three individuals. Persistent elevations of serum creatine kinase (CK) levels were detected in 11 of 12 affected individuals, 1 of whom had an episode of rhabdomyolysis at 20 years of age. Autism spectrum disorder or learning disabilities were reported in four individuals with the c.1567_1587 deletion. Muscle biopsies in eight affected individuals showed mixed myopathic and dystrophic findings, characterized by fiber size variability, internalized nuclei, and slightly increased extracellular connective tissue and inflammation. Immunofluorescence analysis of biopsies from five affected individuals showed reduced α-dystrobrevin immunoreactivity and variably reduced immunoreactivity of other DGC proteins: dystrophin, α, β, δ and γ-sarcoglycans, and α and β-dystroglycans. The DTNA deletion disrupted an interaction between α-dystrobrevin and syntrophin. Specific variants in the coiled-coil domain of DTNA cause skeletal muscle disease with variable penetrance. Affected individuals show a spectrum of clinical manifestations, with severity ranging from hyperCKemia, myalgias, and exercise intolerance to childhood-onset proximal muscle weakness. Our findings expand the molecular etiologies of both muscular dystrophy and paucisymptomatic hyperCKemia, to now include monoallelic DTNA variants as a novel cause of skeletal muscle disease in humans.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37032333,
title = {Participation in a national diagnostic research study: assessing the patient experience},
author = {Lindsay E Rosenfeld and Kimberly LeBlanc and Anna Nagy and Braeden K Ego and  and Alexa T McCray},
doi = {10.1186/s13023-023-02695-5},
issn = {1750-1172},
year  = {2023},
date = {2023-04-01},
journal = {Orphanet J Rare Dis},
volume = {18},
number = {1},
pages = {73},
abstract = {INTRODUCTION: The Undiagnosed Diseases Network (UDN), a clinical research study funded by the National Institutes of Health, aims to provide answers for patients with undiagnosed conditions and generate knowledge about underlying disease mechanisms. UDN evaluations involve collaboration between clinicians and researchers and go beyond what is possible in clinical settings. While medical and research outcomes of UDN evaluations have been explored, this is the first formal assessment of the patient and caregiver experience.nnMETHODS: We invited UDN participants and caregivers to participate in focus groups via email, newsletter, and a private participant Facebook group. We developed focus group questions based on research team expertise, literature focused on patients with rare and undiagnosed conditions, and UDN participant and family member feedback. In March 2021, we conducted, recorded, and transcribed four 60-min focus groups via Zoom. Transcripts were evaluated using a thematic analysis approach.nnRESULTS: The adult undiagnosed focus group described the UDN evaluation as validating and an avenue for access to medical providers. They also noted that the experience impacted professional choices and helped them rely on others for support. The adult diagnosed focus group described the healthcare system as not set up for rare disease. In the pediatric undiagnosed focus group, caregivers discussed a continued desire for information and gratitude for the UDN evaluation. They also described an ability to rule out information and coming to terms with not having answers. The pediatric diagnosed focus group discussed how the experience helped them focus on management and improved communication. Across focus groups, adults (undiagnosed/diagnosed) noted the comprehensiveness of the evaluation. Undiagnosed focus groups (adult/pediatric) discussed a desire for ongoing communication and care with the UDN. Diagnosed focus groups (adult/pediatric) highlighted the importance of the diagnosis they received in the UDN. The majority of the focus groups noted a positive future orientation after participation.nnCONCLUSION: Our findings are consistent with prior literature focused on the patient experience of rare and undiagnosed conditions and highlight benefits from comprehensive evaluations, regardless of whether a diagnosis is obtained. Focus group themes also suggest areas for improvement and future research related to the diagnostic odyssey.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36481303,
title = {A concurrent dual analysis of genomic data augments diagnoses: Experiences of 2 clinical sites in the Undiagnosed Diseases Network},
author = {Rebecca C Spillmann and Queenie K-G Tan and Chloe Reuter and Kelly Schoch and  and Jennefer Kohler and Devon Bonner and Diane Zastrow and Anna Alkelai and Evan Baugh and Heidi Cope and Shruti Marwaha and Matthew T Wheeler and Jonathan A Bernstein and Vandana Shashi and },
doi = {10.1016/j.gim.2022.12.001},
issn = {1530-0366},
year  = {2023},
date = {2023-04-01},
journal = {Genet Med},
volume = {25},
number = {4},
pages = {100353},
abstract = {PURPOSE: Next-generation sequencing (NGS) has revolutionized the diagnostic process for rare/ultrarare conditions. However, diagnosis rates differ between analytical pipelines. In the National Institutes of Health-Undiagnosed Diseases Network (UDN) study, each individual's NGS data are concurrently analyzed by the UDN sequencing core laboratory and the clinical sites. We examined the outcomes of this practice.nnMETHODS: A retrospective review was performed at 2 UDN clinical sites to compare the variants and diagnoses/candidate genes identified with the dual analyses of the NGS data.nnRESULTS: In total, 95 individuals had 100 diagnoses/candidate genes. There was 59% concordance between the UDN sequencing core laboratories and the clinical sites in identifying diagnoses/candidate genes. The core laboratory provided more diagnoses, whereas the clinical sites prioritized more research variants/candidate genes (P < .001). The clinical sites solely identified 15% of the diagnoses/candidate genes. The differences between the 2 pipelines were more often because of variant prioritization disparities than variant detection.nnCONCLUSION: The unique dual analysis of NGS data in the UDN synergistically enhances outcomes. The core laboratory provided a clinical analysis with more diagnoses and the clinical sites prioritized more research variants/candidate genes. Implementing such concurrent dual analyses in other genomic research studies and clinical settings can improve both variant detection and prioritization.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37071725,
title = {Familial Hypercholesterolemia in the Electronic Medical Records and Genomics Network: Prevalence, Penetrance, Cardiovascular Risk, and Outcomes After Return of Results},
author = {Ozan Dikilitas and Alborz Sherafati and Seyedmohammad Saadatagah and Benjamin A Satterfield and David C Kochan and Katherine C Anderson and Wendy K Chung and Scott J Hebbring and Zachary M Salvati and Richard R Sharp and Amy C Sturm and Richard A Gibbs and Robb Rowley and Eric Venner and Jodell E Linder and Laney K Jones and Emma F Perez and Josh F Peterson and Gail P Jarvik and Heidi L Rehm and Hana Zouk and Dan M Roden and Marc S Williams and Teri A Manolio and Iftikhar J Kullo},
doi = {10.1161/CIRCGEN.122.003816},
issn = {2574-8300},
year  = {2023},
date = {2023-04-01},
journal = {Circ Genom Precis Med},
volume = {16},
number = {2},
pages = {e003816},
abstract = {BACKGROUND: The implications of secondary findings detected in large-scale sequencing projects remain uncertain. We assessed prevalence and penetrance of pathogenic familial hypercholesterolemia (FH) variants, their association with coronary heart disease (CHD), and 1-year outcomes following return of results in phase III of the electronic medical records and genomics network.nnMETHODS: Adult participants (n=18 544) at 7 sites were enrolled in a prospective cohort study to assess the clinical impact of returning results from targeted sequencing of 68 actionable genes, including , , and . FH variant prevalence and penetrance (defined as low-density lipoprotein cholesterol >155 mg/dL) were estimated after excluding participants enrolled on the basis of hypercholesterolemia. Multivariable logistic regression was used to estimate the odds of CHD compared to age- and sex-matched controls without FH-associated variants. Process (eg, referral to a specialist or ordering new tests), intermediate (eg, new diagnosis of FH), and clinical (eg, treatment modification) outcomes within 1 year after return of results were ascertained by electronic health record review.nnRESULTS: The prevalence of FH-associated pathogenic variants was 1 in 188 (69 of 13,019 unselected participants). Penetrance was 87.5%. The presence of an FH variant was associated with CHD (odds ratio, 3.02 [2.00-4.53]) and premature CHD (odds ratio, 3.68 [2.34-5.78]). At least 1 outcome occurred in 92% of participants; 44% received a new diagnosis of FH and 26% had treatment modified following return of results.nnCONCLUSIONS: In a multisite cohort of electronic health record-linked biobanks, monogenic FH was prevalent, penetrant, and associated with presence of CHD. Nearly half of participants with an FH-associated variant received a new diagnosis of FH and a quarter had treatment modified after return of results. These results highlight the potential utility of sequencing electronic health record-linked biobanks to detect FH.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36789775,
title = {Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke},
author = {Ernst Mayerhofer and Christoph Strecker and Heiko Becker and Marios K Georgakis and Md Mesbah Uddin and Michael M Hoffmann and Niroshan Nadarajah and Manja Meggendorfer and Torsten Haferlach and Jonathan Rosand and Pradeep Natarajan and Christopher D Anderson and Andreas Harloff and Gregor Hoermann},
doi = {10.1161/STROKEAHA.122.041416},
issn = {1524-4628},
year  = {2023},
date = {2023-04-01},
journal = {Stroke},
volume = {54},
number = {4},
pages = {938--946},
abstract = {BACKGROUND: Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment.nnMETHODS: We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation.nnRESULTS: We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; <0.001 for both). Patients with CHIP were older (median [interquartile range], 53 [50-59] versus 51 [41-56] years; <0.001), had higher carotid intima-media thickness (0.68 [0.58-0.80] versus 0.59 [0.51-0.73] mm; =0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; =0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy.nnCONCLUSIONS: Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37082147,
title = {Convergent coexpression of autism-associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies},
author = {Calwing Liao and Mariana Moyses-Oliveira and Celine E F De Esch and Riya Bhavsar and Xander Nuttle and Aiqun Li and Alex Yu and Nicholas D Burt and Serkan Erdin and Jack M Fu and Minghui Wang and Theodore Morley and Lide Han and  and Patrick A Dion and Guy A Rouleau and Bin Zhang and Kristen J Brennand and Michael E Talkowski and Douglas M Ruderfer},
doi = {10.1016/j.xgen.2023.100277},
issn = {2666-979X},
year  = {2023},
date = {2023-04-01},
journal = {Cell Genom},
volume = {3},
number = {4},
pages = {100277},
abstract = {Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein-altering variants in many genes have been shown to contribute to ASD; however, understanding the convergence across many genes remains a challenge. We demonstrate that coexpression patterns from 993 human postmortem brains are significantly correlated with the transcriptional consequences of CRISPR perturbations in human neurons. Across 71 ASD risk genes, there was significant tissue-specific convergence implicating synaptic pathways. Tissue-specific convergence was further demonstrated across schizophrenia and atrial fibrillation risk genes. The degree of ASD convergence was significantly correlated with ASD association from rare variation and differential expression in ASD brains. Positively convergent genes showed intolerance to functional mutations and had shorter coding lengths than known risk genes even after removing association with ASD. These results indicate that convergent coexpression can identify potentially novel genes that are unlikely to be discovered by sequencing studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37022688,
title = {Classifying Firearm Injury Using EHR Data-Finding the Phenotype by Reading the Notes},
author = {Roy H Perlis},
doi = {10.1001/jamanetworkopen.2023.5781},
issn = {2574-3805},
year  = {2023},
date = {2023-04-01},
journal = {JAMA Netw Open},
volume = {6},
number = {4},
pages = {e235781},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36859734,
title = {Author Correction: Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains},
author = {Ditte Demontis and G Bragi Walters and Georgios Athanasiadis and Raymond Walters and Karen Therrien and Trine Tollerup Nielsen and Leila Farajzadeh and Georgios Voloudakis and Jaroslav Bendl and Biau Zeng and Wen Zhang and Jakob Grove and Thomas D Als and Jinjie Duan and F Kyle Satterstrom and Jonas Bybjerg-Grauholm and Marie Bækved-Hansen and Olafur O Gudmundsson and Sigurdur H Magnusson and Gisli Baldursson and Katrin Davidsdottir and Gyda S Haraldsdottir and Esben Agerbo and Gabriel E Hoffman and Søren Dalsgaard and Jonna Martin and Marta Ribasés and Dorret I Boomsma and Maria Soler Artigas and Nina Roth Mota and Daniel Howrigan and Sarah E Medland and Tetyana Zayats and Veera M Rajagopal and  and  and Merete Nordentoft and Ole Mors and David M Hougaard and Preben Bo Mortensen and Mark J Daly and Stephen V Faraone and Hreinn Stefansson and Panos Roussos and Barbara Franke and Thomas Werge and Benjamin M Neale and Kari Stefansson and Anders D Børglum},
doi = {10.1038/s41588-023-01350-w},
issn = {1546-1718},
year  = {2023},
date = {2023-04-01},
journal = {Nat Genet},
volume = {55},
number = {4},
pages = {730},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37066248,
title = {Prediction and stratification of longitudinal risk for chronic obstructive pulmonary disease across smoking behaviors},
author = {Yixuan He and David C Qian and James A Diao and Michael H Cho and Edwin K Silverman and Alexander Gusev and Arjun K Manrai and Alicia R Martin and Chirag J Patel},
doi = {10.1101/2023.04.04.23288086},
year  = {2023},
date = {2023-04-01},
journal = {medRxiv},
abstract = {Smoking is the leading risk factor for chronic obstructive pulmonary disease (COPD) worldwide, yet many people who never smoke develop COPD. We hypothesize that considering other socioeconomic and environmental factors can better predict and stratify the risk of COPD in both non-smokers and smokers. We performed longitudinal analysis of COPD in the UK Biobank to develop the Socioeconomic and Environmental Risk Score (SERS) which captures additive and cumulative environmental, behavioral, and socioeconomic exposure risks beyond tobacco smoking. We tested the ability of SERS to predict and stratify the risk of COPD in current, previous, and never smokers of European and non-European ancestries in comparison to a composite genome-wide polygenic risk score (PGS). We tested associations using Cox regression models and assessed the predictive performance of models using Harrell's C index. SERS (C index = 0.770, 95% CI 0.756 to 0.784) was more predictive of COPD than smoking status (C index = 0.738, 95% CI 0.724 to 0.752), pack-years (C index = 0.742, 95% CI 0.727 to 0.756). Compared to the remaining population, individuals in the highest decile of the SERS had hazard ratios (HR) = 7.24 (95% CI 6.51 to 8.05, P < 0.0001) for incident COPD. Never smokers in the highest decile of exposure risk were more likely to develop COPD than previous and current smokers in the lowest decile with HR=4.95 (95% CI 1.56 to 15.69, P=6.65×10  ) and 2.92 (95%CI 1.51 to 5.61, P=1.38×10  ), respectively. In general, the prediction accuracy of SERS was lower in the non-European populations compared to the European evaluation set. In addition to genetic factors, socioeconomic and environmental factors beyond smoking can predict and stratify COPD risk for both non- and smoking individuals. Smoking status is often considered in screening; other non-smoking environmental and non-genetic variables should be evaluated prospectively for their clinical utility.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37019892,
title = {Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy},
author = {Arne Lauer and Samantha L Speroni and Myoung Choi and Xiao Da and Christine Duncan and Siobhan McCarthy and Vijai Krishnan and Cole A Lusk and David Rohde and Mikkel Bo Hansen and Jayashree Kalpathy-Cramer and Daniel J Loes and Paul A Caruso and David A Williams and Kim Mouridsen and Kyrre E Emblem and Florian S Eichler and Patricia L Musolino},
doi = {10.1038/s41467-023-37262-w},
issn = {2041-1723},
year  = {2023},
date = {2023-04-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {1900},
abstract = {Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation. We found widespread and sustained normalization of white matter permeability and microvascular flow. We demonstrate that ABCD1 functional bone marrow-derived cells can engraft in the cerebral vascular and perivascular space. Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37066311,
title = {Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate},
author = {Kelsey Robinson and Trenell J Mosley and Kenneth S Rivera-González and Christopher R Jabbarpour and Sarah W Curtis and Wasiu Lanre Adeyemo and Terri H Beaty and Azeez Butali and Carmen J Buxó and David J Cutler and Michael P Epstein and Lord Jj Gowans and Jacqueline T Hecht and Jeffrey C Murray and Gary M Shaw and Lina Moreno Uribe and Seth M Weinberg and Harrison Brand and Mary L Marazita and Robert J Lipinski and Elizabeth J Leslie},
doi = {10.1101/2023.03.01.23286642},
year  = {2023},
date = {2023-04-01},
journal = {medRxiv},
abstract = {Orofacial clefts (OFCs) are the most common craniofacial birth defects and are often categorized into two etiologically distinct groups: cleft lip with or without cleft palate (CL/P) and isolated cleft palate (CP). CP is highly heritable, but there are still relatively few established genetic risk factors associated with its occurrence compared to CL/P. Historically, CP has been studied as a single phenotype despite manifesting across a spectrum of defects involving the hard and/or soft palate. We performed GWAS using transmission disequilibrium tests using 435 case-parent trios to evaluate broad risks for any cleft palate (ACP, n=435), as well as subtype-specific risks for any cleft soft palate (CSP, n=259) and any cleft hard palate (CHP, n=125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p=4.24×10  ) associated with CHP. One gene at this locus, angiopoietin-like 2 (  ), plays a role in osteoblast differentiation. It is expressed in craniofacial tissue of human embryos, as well as in the developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p<5×10  ), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios (ORs) for each of the 20 loci were most similar across all three groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either the CSP or CHP groups. We also found nominal evidence of replication (p<0.05) for 22 SNPs previously associated with cleft palate (including CL/P). Interestingly, most SNPs associated with CL/P cases were found to convey the opposite effect in those replicated in our dataset for CP only. Ours is the first study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37162822,
title = {Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage},
author = {Livia Parodi and Mary E Comeau and Marios K Georgakis and Ernst Mayerhofer and Jaeyoon Chung and Guido J Falcone and Rainer Malik and Stacie L Demel and Bradford B Worrall and Sebastian Koch and Fernando D Testai and Steven J Kittner and Jacob L McCauley and Christiana E Hall and Douglas J Mayson and Mitchell Sv Elkind and Michael L James and Daniel Woo and Jonathan Rosand and Carl D Langefeld and Christopher D Anderson},
doi = {10.1101/2023.04.18.23288754},
year  = {2023},
date = {2023-04-01},
journal = {medRxiv},
abstract = {OBJECTIVE: Genome-wide association studies have identified  as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of  in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.nnMETHODS: 95,000 base pairs spanning  , including  and  /  were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at  could be causally related to ICH risk.nnRESULTS: Common and rare variant analyses prioritized variants in  5'-UTR and  intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that  is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the  -promoter and  -enhancer regions prioritized by association testing. MVMR analyses demonstrated that  overexpression could be causally related to non-lobar ICH risk.nnINTERPRETATION: Altered promoter-enhancer interactions leading to  overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at  , offering a potential new target for prevention of ICH and CSVD.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid37100858,
title = {AI-assisted prediction of differential response to antidepressant classes using electronic health records},
author = {Yi-Han Sheu and Colin Magdamo and Matthew Miller and Sudeshna Das and Deborah Blacker and Jordan W Smoller},
doi = {10.1038/s41746-023-00817-8},
issn = {2398-6352},
year  = {2023},
date = {2023-04-01},
journal = {NPJ Digit Med},
volume = {6},
number = {1},
pages = {73},
abstract = {Antidepressant selection is largely a trial-and-error process. We used electronic health record (EHR) data and artificial intelligence (AI) to predict response to four antidepressants classes (SSRI, SNRI, bupropion, and mirtazapine) 4 to 12 weeks after antidepressant initiation. The final data set comprised 17,556 patients. Predictors were derived from both structured and unstructured EHR data and models accounted for features predictive of treatment selection to minimize confounding by indication. Outcome labels were derived through expert chart review and AI-automated imputation. Regularized generalized linear model (GLM), random forest, gradient boosting machine (GBM), and deep neural network (DNN) models were trained and their performance compared. Predictor importance scores were derived using SHapley Additive exPlanations (SHAP). All models demonstrated similarly good prediction performance (AUROCs ≥ 0.70, AUPRCs ≥ 0.68). The models can estimate differential treatment response probabilities both between patients and between antidepressant classes for the same patient. In addition, patient-specific factors driving response probabilities for each antidepressant class can be generated. We show that antidepressant response can be accurately predicted from real-world EHR data with AI modeling, and our approach could inform further development of clinical decision support systems for more effective treatment selection.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36739622,
title = {The sleep and wake electroencephalogram over the lifespan},
author = {Haoqi Sun and Elissa Ye and Luis Paixao and Wolfgang Ganglberger and Catherine J Chu and Can Zhang and Jonathan Rosand and Emmanuel Mignot and Sydney S Cash and David Gozal and Robert J Thomas and M Brandon Westover},
doi = {10.1016/j.neurobiolaging.2023.01.006},
issn = {1558-1497},
year  = {2023},
date = {2023-04-01},
journal = {Neurobiol Aging},
volume = {124},
pages = {60--70},
abstract = {Both sleep and wake encephalograms (EEG) change over the lifespan. While prior studies have characterized age-related changes in the EEG, the datasets span a particular age group, or focused on sleep and wake macrostructure rather than the microstructure. Here, we present sex-stratified data from 3372 community-based or clinic-based otherwise neurologically and psychiatrically healthy participants ranging from 11 days to 80 years of age. We estimate age norms for key sleep and wake EEG parameters including absolute and relative powers in delta, theta, alpha, and sigma bands, as well as sleep spindle density, amplitude, duration, and frequency. To illustrate the potential use of the reference measures developed herein, we compare them to sleep EEG recordings from age-matched participants with Alzheimer's disease, severe sleep apnea, depression, osteoarthritis, and osteoporosis. Although the partially clinical nature of the datasets may bias the findings towards less normal and hence may underestimate pathology in practice, age-based EEG reference values enable objective screening of deviations from healthy aging among individuals with a variety of disorders that affect brain health.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36743383,
title = {Post-traumatic growth in PhD students during the COVID-19 pandemic},
author = {Allison K Tu and Juliana Restivo Haney and Kathryn O'Neill and Akshay Swaminathan and Karmel W Choi and Hyunjoon Lee and Jordan W Smoller and Vikram Patel and Paul J Barreira and Cindy H Liu and John A Naslund},
doi = {10.1016/j.psycom.2023.100104},
issn = {2772-5987},
year  = {2023},
date = {2023-03-01},
journal = {Psychiatry Res Commun},
volume = {3},
number = {1},
pages = {100104},
abstract = {Throughout the COVID-19 pandemic, graduate students have faced increased risk of mental health challenges. Research suggests that experiencing adversity may induce positive psychological changes, called post-traumatic growth (PTG). These changes can include improved relationships with others, perceptions of oneself, and enjoyment of life. Few existing studies have explored this phenomenon among graduate students. This secondary data analysis of a survey conducted in November 2020 among graduate students at a private R1 University in the northeast United States examined graduate students' levels and correlates of PTG during the COVID-19 pandemic. Students had a low level of PTG, with a mean score of 10.31 out of 50. Linear regression models showed significant positive relationships between anxiety and PTG and between a measure of self-reported impact of the pandemic and PTG. Non-White minorities also had significantly greater PTG than White participants. Experiencing more negative impact due to the pandemic and ruminating about the pandemic were correlated with greater PTG. These findings advance research on the patterns of PTG during the COVID-19 pandemic and can inform future studies of graduate students' coping mechanisms and support efforts to promote pandemic recovery and resilience.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36951861,
title = {Sex-Specific Neurodevelopmental Outcomes Among Offspring of Mothers With SARS-CoV-2 Infection During Pregnancy},
author = {Andrea G Edlow and Victor M Castro and Lydia L Shook and Sebastien Haneuse and Anjali J Kaimal and Roy H Perlis},
doi = {10.1001/jamanetworkopen.2023.4415},
issn = {2574-3805},
year  = {2023},
date = {2023-03-01},
journal = {JAMA Netw Open},
volume = {6},
number = {3},
pages = {e234415},
abstract = {IMPORTANCE: Prior studies using large registries have suggested a modest increase in risk for neurodevelopmental diagnoses among children of mothers with immune activation during pregnancy, and such risk may be sex-specific.nnOBJECTIVE: To determine whether in utero exposure to SARS-CoV-2 is associated with sex-specific risk for neurodevelopmental disorders up to 18 months after birth, compared with unexposed offspring born during or prior to the COVID-19 pandemic period.nnDESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included the live offspring of all mothers who delivered between January 1 and December 31, 2018 (born and followed up before the COVID-19 pandemic), between March 1 and December 31, 2019 (born before and followed up during the COVID-19 pandemic), and between March 1, 2020, and May 31, 2021 (born and followed up during the COVID-19 pandemic). Offspring were born at any of 8 hospitals across 2 health systems in Massachusetts.nnEXPOSURES: Polymerase chain reaction evidence of maternal SARS-CoV-2 infection during pregnancy.nnMAIN OUTCOMES AND MEASURES: Electronic health record documentation of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes corresponding to neurodevelopmental disorders.nnRESULTS: The COVID-19 pandemic cohort included 18 355 live births (9399 boys [51.2%]), including 883 (4.8%) with maternal SARS-CoV-2 positivity during pregnancy. The cohort included 1809 Asian individuals (9.9%), 1635 Black individuals (8.9%), 12 718 White individuals (69.3%), and 1714 individuals (9.3%) who were of other race (American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, more than 1 race); 2617 individuals (14.3%) were of Hispanic ethnicity. Mean maternal age was 33.0 (IQR, 30.0-36.0) years. In adjusted regression models accounting for race, ethnicity, insurance status, hospital type (academic center vs community), maternal age, and preterm status, maternal SARS-CoV-2 positivity was associated with a statistically significant elevation in risk for neurodevelopmental diagnoses at 12 months among male offspring (adjusted OR, 1.94 [95% CI 1.12-3.17]; P = .01) but not female offspring (adjusted OR, 0.89 [95% CI, 0.39-1.76]; P = .77). Similar effects were identified using matched analyses in lieu of regression. At 18 months, more modest effects were observed in male offspring (adjusted OR, 1.42 [95% CI, 0.92-2.11]; P = .10).nnCONCLUSIONS AND RELEVANCE: In this cohort study of offspring with SARS-CoV-2 exposure in utero, such exposure was associated with greater magnitude of risk for neurodevelopmental diagnoses among male offspring at 12 months following birth. As with prior studies of maternal infection, substantially larger cohorts and longer follow-up will be required to reliably estimate or refute risk.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36203014,
title = {Precise DNA cleavage using CRISPR-SpRYgests},
author = {Kathleen A Christie and Jimmy A Guo and Rachel A Silverstein and Roman M Doll and Megumu Mabuchi and Hannah E Stutzman and Jiecong Lin and Linyuan Ma and Russell T Walton and Luca Pinello and G Brett Robb and Benjamin P Kleinstiver},
doi = {10.1038/s41587-022-01492-y},
issn = {1546-1696},
year  = {2023},
date = {2023-03-01},
journal = {Nat Biotechnol},
volume = {41},
number = {3},
pages = {409--416},
abstract = {Methods for in vitro DNA cleavage and molecular cloning remain unable to precisely cleave DNA directly adjacent to bases of interest. Restriction enzymes (REs) must bind specific motifs, whereas wild-type CRISPR-Cas9 or CRISPR-Cas12 nucleases require protospacer adjacent motifs (PAMs). Here we explore the utility of our previously reported near-PAMless SpCas9 variant, named SpRY, to serve as a universal DNA cleavage tool for various cloning applications. By performing SpRY DNA digests (SpRYgests) using more than 130 guide RNAs (gRNAs) sampling a wide diversity of PAMs, we discovered that SpRY is PAMless in vitro and can cleave DNA at practically any sequence, including sites refractory to cleavage with wild-type SpCas9. We illustrate the versatility and effectiveness of SpRYgests to improve the precision of several cloning workflows, including those not possible with REs or canonical CRISPR nucleases. We also optimize a rapid and simple one-pot gRNA synthesis protocol to streamline SpRYgest implementation. Together, SpRYgests can improve various DNA engineering applications that benefit from precise DNA breaks.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36480766,
title = {Clonal Hematopoiesis and Risk of Incident Lung Cancer},
author = {Ruiyi Tian and Brian Wiley and Jie Liu and Xiaoyu Zong and Buu Truong and Stephanie Zhao and Md Mesbah Uddin and Abhishek Niroula and Christopher A Miller and Semanti Mukherjee and Brendan T Heiden and Jingqin Luo and Varun Puri and Benjamin D Kozower and Matthew J Walter and Li Ding and Daniel C Link and Christopher I Amos and Benjamin L Ebert and Ramaswamy Govindan and Pradeep Natarajan and Kelly L Bolton and Yin Cao},
doi = {10.1200/JCO.22.00857},
issn = {1527-7755},
year  = {2023},
date = {2023-03-01},
journal = {J Clin Oncol},
volume = {41},
number = {7},
pages = {1423--1433},
abstract = {PURPOSE: To prospectively examine the association between clonal hematopoiesis (CH) and subsequent risk of lung cancer.nnMETHODS: Among 200,629 UK Biobank (UKBB) participants with whole-exome sequencing, CH was identified in a nested case-control study of 832 incident lung cancer cases and 3,951 controls (2006-2019) matched on age and year at blood draw, sex, race, and smoking status. A similar nested case-control study (141 cases/652 controls) was conducted among 27,975 participants with whole-exome sequencing in the Mass General Brigham Biobank (MGBB, 2010-2021). In parallel, we compared CH frequency in published data from 5,003 patients with solid tumor (2,279 lung cancer) who had pretreatment blood sequencing performed through Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets.nnRESULTS: In UKBB, the presence of CH was associated with increased risk of lung cancer (cases: 12.5%  controls: 8.7%; multivariable-adjusted odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74). The association remained robust after excluding participants with chronic obstructive pulmonary disease. No significant interactions with known risk factors, including polygenic risk score and C-reactive protein, were identified. In MGBB, we observed similar enrichment of CH in lung cancer (cases: 15.6%  controls: 12.7%). The meta-analyzed OR (95% CI) of UKBB and MGBB was 1.35 (1.08 to 1.68) for CH overall and 1.61 (1.19 to 2.18) for variant allele frequencies ≥ 10%. In Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, CH with a variant allele frequency ≥ 10% was enriched in pretreatment lung cancer compared with other tumors after adjusting for age, sex, and smoking (OR for lung  breast cancer: 1.61; 95% CI, 1.03 to 2.53).nnCONCLUSION: Independent of known risk factors, CH is associated with increased risk of lung cancer.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36241009,
title = {Clonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population},
author = {Bryan Kestenbaum and Alexander G Bick and Caitlyn Vlasschaert and Michael J Rauh and Matthew B Lanktree and Nora Franceschini and Moore B Shoemaker and Raymond C Harris and Bruce M Psaty and Anna Köttgen and Pradeep Natarajan and Cassianne Robinson-Cohen},
doi = {10.1053/j.ajkd.2022.08.014},
issn = {1523-6838},
year  = {2023},
date = {2023-03-01},
journal = {Am J Kidney Dis},
volume = {81},
number = {3},
pages = {329--335},
abstract = {RATIONALE & OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.nnSTUDY DESIGN: Cohort study.nnSETTING & PARTICIPANTS: 12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.nnEXPOSURE: CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.nnOUTCOME: Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.nnANALYTICAL APPROACH: Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.nnRESULTS: The median baseline eGFR was 84mL/min/1.73m. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m, of age above or below 60 years, or with or without diabetes.nnLIMITATIONS: Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.nnCONCLUSIONS: We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36275200,
title = {Identifying Novel Genes and Variants in Immune and Coagulation Pathways Associated with Macular Degeneration},
author = {Tianxiao Huan and Shun-Yun Cheng and Bo Tian and Claudio Punzo and Haijiang Lin and Mark Daly and Johanna M Seddon},
doi = {10.1016/j.xops.2022.100206},
issn = {2666-9145},
year  = {2023},
date = {2023-03-01},
journal = {Ophthalmol Sci},
volume = {3},
number = {1},
pages = {100206},
abstract = {PURPOSE: To select individuals and families with a low genetic burden for age-related macular degeneration (AMD), to inform the clinical diagnosis of macular disorders, and to find novel genetic variants associated with maculopathies.nnDESIGN: Genetic association study based on targeted and whole-exome sequencing.nnPARTICIPANTS: A total of 758 subjects (481 individuals with maculopathy and 277 controls), including 316 individuals in 72 families.nnMETHODS: We focused on 150 genes involved in the complement, coagulation, and inflammatory pathways. Single-variant tests were performed on 7755 variants shared among ≥ 5 subjects using logistic regression. Gene-based tests were used to evaluate aggregate effects from rare and low-frequency variants (at minor allele frequency [MAF] ≤ 5% or ≤ 1%) in a gene using burden tests. For families whose affected members had a low burden of genetic risk based on known common and rare variants related to AMD, we searched for rare variants (MAF < 0.001) whose risk alleles occurred in ≥ 80% of affected individuals but not in controls. Immunohistochemistry was performed to determine the protein expression of a novel gene ( []) in retinal tissues.nnMAIN OUTCOME MEASURES: Genotypes and phenotypes of macular degeneration.nnRESULTS: We confirmed the association of a synonymous variant in  (Ala473, rs2274700, proxy to intronic rs1410996,    = 1) with maculopathy (odds ratio, 0.64;  = 4.5 × 10). Higher AMD polygenic risk scores (PRSs) were associated with intermediate and advanced AMD. Among families with low PRSs and no known rare variants for maculopathy, we identified 2 novel, highly penetrant missense rare variants in  A disintegrin and metalloprotease,  (p.Arg288Cys) and  (p.Leu289Arg). Immunohistochemistry analyses revealed F2RL2 protein expression in cone photoreceptor outer segments and Müller glia cells of human and pig retinas. Coagulation factor II thrombin receptor-like 2 expression appeared increased in fibrotic areas in advanced AMD samples with neovascularization, suggesting that  may play a role in the progression to advanced macular disease.nnCONCLUSIONS: New missense rare variants in the genes  and  were associated with maculopathies. Results suggest that novel genes related to the coagulation and immune pathways may be involved in the pathogenesis of macular diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36802703,
title = {Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program},
author = {Aeron M Small and Gina M Peloso and Jason Linefsky and Jayashri Aragam and Ashley Galloway and Vidisha Tanukonda and Lu-Chen Wang and Zhi Yu and Margaret Sunitha Selvaraj and Eric H Farber-Eger and Michael T Baker and Shefali Setia-Verma and Simon S K Lee and Michael Preuss and Marylyn D Ritchie and Scott M Damrauer and Daniel J Rader and Quinn S Wells and Ruth Loos and Steven A Lubitz and George Thanassoulis and Kelly Cho and Peter W F Wilson and  and Pradeep Natarajan and Christopher J O'Donnell},
doi = {10.1161/CIRCULATIONAHA.122.061451},
issn = {1524-4539},
year  = {2023},
date = {2023-03-01},
journal = {Circulation},
volume = {147},
number = {12},
pages = {942--955},
abstract = {BACKGROUND: Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS.nnMETHODS: We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study.nnRESULTS: We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS () and 6 were novel (). Two novel lead variants were associated in non-White individuals (<0.05): rs12740374 () in Black and Hispanic individuals and rs1522387 () in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [], rs12740374 []) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the  locus. However, the  locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis.nnCONCLUSIONS: We performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37034659,
title = {Proteogenomic integration reveals CXCL10 as a potentially downstream causal mediator for IL-6 signaling on atherosclerosis},
author = {Savvina Prapiadou and Luka Živković and Barbara Thorand and Marc J George and Sander W van der Laan and Rainer Malik and Christian Herder and Wolfgang Koenig and Thor Ueland and Ola Kleveland and Pal Aukrust and Lars Gullestad and Jürgen Bernhagen and Gerard Pasterkamp and Annette Peters and Aroon D Hingorani and Jonathan Rosand and Martin Dichgans and Christopher D Anderson and Marios K Georgakis},
doi = {10.1101/2023.03.24.23287543},
year  = {2023},
date = {2023-03-01},
journal = {medRxiv},
abstract = {BACKGROUND: Genetic and experimental studies support a causal involvement of interleukin-6 (IL-6) signaling in atheroprogression. While trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects.nnMETHODS: Leveraging data from 522,681 individuals, we constructed a genetic instrument of 26 variants in the gene encoding the IL-6 receptor (IL-6R) that proxied for pharmacological IL-6R inhibition. Using Mendelian randomization (MR), we assessed its effects on 3,281 plasma proteins quantified with an aptamer-based assay in the INTERVAL cohort (n=3,301). Using mediation MR, we explored proteomic mediators of the effects of genetically proxied IL-6 signaling on coronary artery disease (CAD), large artery atherosclerotic stroke (LAAS), and peripheral artery disease (PAD). For significant mediators, we tested associations of their circulating levels with incident cardiovascular events in a population-based study (n=1,704) and explored the histological, transcriptomic, and cellular phenotypes correlated with their expression levels in samples from human atherosclerotic lesions.nnRESULTS: We found significant effects of genetically proxied IL-6 signaling on 70 circulating proteins involved in cytokine production/regulation and immune cell recruitment/differentiation, which correlated with the proteomic effects of pharmacological IL-6R inhibition in a clinical trial. Among the 70 significant proteins, genetically proxied circulating levels of CXCL10 were associated with risk of CAD, LAAS, and PAD with up to 67% of the effects of genetically downregulated IL-6 signaling on these endpoints mediated by decreases in CXCL10. Higher midlife circulating CXCL10 levels were associated with a larger number of cardiovascular events over 20 years, whereas higher  expression in human atherosclerotic lesions correlated with a larger lipid core and a transcriptomic profile reflecting immune cell infiltration, adaptive immune system activation, and cytokine signaling.nnCONCLUSIONS: Integrating multiomics data, we found a proteomic signature of IL-6 signaling activation and mediators of its effects on cardiovascular disease. Our analyses suggest the interferon-γ-inducible chemokine CXCL10 to be a potentially causal mediator for atherosclerosis in three vascular compartments and as such could serve as a promising drug target for atheroprotection.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36649075,
title = {A seed sequence variant in miR-145-5p causes multisystem smooth muscle dysfunction syndrome},
author = {Christian Lacks Lino Cardenas and Lauren C Briere and David A Sweetser and Mark E Lindsay and Patricia L Musolino},
doi = {10.1172/JCI166497},
issn = {1558-8238},
year  = {2023},
date = {2023-03-01},
journal = {J Clin Invest},
volume = {133},
number = {5},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36652267,
title = {Evaluation of a Model to Target High-risk Psychiatric Inpatients for an Intensive Postdischarge Suicide Prevention Intervention},
author = {Ronald C Kessler and Mark S Bauer and Todd M Bishop and Robert M Bossarte and Victor M Castro and Olga V Demler and Sarah M Gildea and Joseph L Goulet and Andrew J King and Chris J Kennedy and Sara J Landes and Howard Liu and Alex Luedtke and Patrick Mair and Brian P Marx and Matthew K Nock and Maria V Petukhova and Wilfred R Pigeon and Nancy A Sampson and Jordan W Smoller and Aletha Miller and Gretchen Haas and Jeffrey Benware and John Bradley and Richard R Owen and Samuel House and Snezana Urosevic and Lauren M Weinstock},
doi = {10.1001/jamapsychiatry.2022.4634},
issn = {2168-6238},
year  = {2023},
date = {2023-03-01},
journal = {JAMA Psychiatry},
volume = {80},
number = {3},
pages = {230--240},
abstract = {IMPORTANCE: The months after psychiatric hospital discharge are a time of high risk for suicide. Intensive postdischarge case management, although potentially effective in suicide prevention, is likely to be cost-effective only if targeted at high-risk patients. A previously developed machine learning (ML) model showed that postdischarge suicides can be predicted from electronic health records and geospatial data, but it is unknown if prediction could be improved by adding additional information.nnOBJECTIVE: To determine whether model prediction could be improved by adding information extracted from clinical notes and public records.nnDESIGN, SETTING, AND PARTICIPANTS: Models were trained to predict suicides in the 12 months after Veterans Health Administration (VHA) short-term (less than 365 days) psychiatric hospitalizations between the beginning of 2010 and September 1, 2012 (299 050 hospitalizations, with 916 hospitalizations followed within 12 months by suicides) and tested in the hospitalizations from September 2, 2012, to December 31, 2013 (149 738 hospitalizations, with 393 hospitalizations followed within 12 months by suicides). Validation focused on net benefit across a range of plausible decision thresholds. Predictor importance was assessed with Shapley additive explanations (SHAP) values. Data were analyzed from January to August 2022.nnMAIN OUTCOMES AND MEASURES: Suicides were defined by the National Death Index. Base model predictors included VHA electronic health records and patient residential data. The expanded predictors came from natural language processing (NLP) of clinical notes and a social determinants of health (SDOH) public records database.nnRESULTS: The model included 448 788 unique hospitalizations. Net benefit over risk horizons between 3 and 12 months was generally highest for the model that included both NLP and SDOH predictors (area under the receiver operating characteristic curve range, 0.747-0.780; area under the precision recall curve relative to the suicide rate range, 3.87-5.75). NLP and SDOH predictors also had the highest predictor class-level SHAP values (proportional SHAP = 64.0% and 49.3%, respectively), although the single highest positive variable-level SHAP value was for a count of medications classified by the US Food and Drug Administration as increasing suicide risk prescribed the year before hospitalization (proportional SHAP = 15.0%).nnCONCLUSIONS AND RELEVANCE: In this study, clinical notes and public records were found to improve ML model prediction of suicide after psychiatric hospitalization. The model had positive net benefit over 3-month to 12-month risk horizons for plausible decision thresholds. Although caution is needed in inferring causality based on predictor importance, several key predictors have potential intervention implications that should be investigated in future studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36865265,
title = {Integrative polygenic risk score improves the prediction accuracy of complex traits and diseases},
author = {Buu Truong and Leland E Hull and Yunfeng Ruan and Qin Qin Huang and Whitney Hornsby and Hilary C Martin and David A van Heel and Ying Wang and Alicia R Martin and Hong Lee and Pradeep Natarajan},
doi = {10.1101/2023.02.21.23286110},
year  = {2023},
date = {2023-03-01},
journal = {medRxiv},
abstract = {Polygenic risk scores (PRS) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. Validation and transferability of existing PRS across independent datasets and diverse ancestries are limited, which hinders the practical utility and exacerbates health disparities. We propose PRSmix, a framework that evaluates and leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture. We applied PRSmix to 47 and 32 diseases/traits in European and South Asian ancestries, respectively. PRSmix demonstrated a mean prediction accuracy improvement of 1.20-fold (95% CI: [1.10; 1.3]; P-value = 9.17 x 10-5) and 1.19-fold (95% CI: [1.11; 1.27]; P-value = 1.92 x 10-6), and PRSmix+ improved the prediction accuracy by 1.72-fold (95% CI: [1.40; 2.04]; P-value = 7.58 x 10-6) and 1.42-fold (95% CI: [1.25; 1.59]; P-value = 8.01 x 10-7) in European and South Asian ancestries, respectively. Compared to the previously established cross-trait-combination method with scores from pre-defined correlated traits, we demonstrated that our method can improve prediction accuracy for coronary artery disease up to 3.27-fold (95% CI: [2.1; 4.44]; P-value after FDR correction = 2.6 x 10-4). Our method provides a comprehensive framework to benchmark and leverage the combined power of PRS for maximal performance in a desired target population.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36655558,
title = {Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity},
author = {Mark K Bakker and Jos P Kanning and Gad Abraham and Amy E Martinsen and Bendik S Winsvold and John-Anker Zwart and Romain Bourcier and Tomonobu Sawada and Masaru Koido and Yoichiro Kamatani and Sandrine Morel and Philippe Amouyel and Stéphanie Debette and Philippe Bijlenga and Takiy Berrandou and Santhi K Ganesh and Nabila Bouatia-Naji and Gregory Jones and Matthew Bown and Gabriel J E Rinkel and Jan H Veldink and Ynte M Ruigrok and },
doi = {10.1161/STROKEAHA.122.040715},
issn = {1524-4628},
year  = {2023},
date = {2023-03-01},
journal = {Stroke},
volume = {54},
number = {3},
pages = {810--818},
abstract = {BACKGROUND: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics.nnMETHODS: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients.nnRESULTS: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10 per year [95% CI, -6.49×10 to -3.14×10]; =1.82×10), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; =0.0041).nnCONCLUSIONS: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36914870,
title = {Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations},
author = {Dongjing Liu and Dara Meyer and Brian Fennessy and Claudia Feng and Esther Cheng and Jessica S Johnson and You Jeong Park and Marysia-Kolbe Rieder and Steven Ascolillo and Agathe de Pins and Amanda Dobbyn and Dannielle Lebovitch and Emily Moya and Tan-Hoang Nguyen and Lillian Wilkins and Arsalan Hassan and  and Katherine E Burdick and Joseph D Buxbaum and Enrico Domenici and Sophia Frangou and Annette M Hartmann and Claudine Laurent-Levinson and Dheeraj Malhotra and Carlos N Pato and Michele T Pato and Kerry Ressler and Panos Roussos and Dan Rujescu and Celso Arango and Alessandro Bertolino and Giuseppe Blasi and Luisella Bocchio-Chiavetto and Dominique Campion and Vaughan Carr and Janice M Fullerton and Massimo Gennarelli and Javier González-Peñas and Douglas F Levinson and Bryan Mowry and Vishwajit L Nimgaokar and Giulio Pergola and Antonio Rampino and Jorge A Cervilla and Margarita Rivera and Sibylle G Schwab and Dieter B Wildenauer and Mark Daly and Benjamin Neale and Tarjinder Singh and Michael C O'Donovan and Michael J Owen and James T Walters and Muhammad Ayub and Anil K Malhotra and Todd Lencz and Patrick F Sullivan and Pamela Sklar and Eli A Stahl and Laura M Huckins and Alexander W Charney},
doi = {10.1038/s41588-023-01305-1},
issn = {1546-1718},
year  = {2023},
date = {2023-03-01},
journal = {Nat Genet},
volume = {55},
number = {3},
pages = {369--376},
abstract = {Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36925354,
title = {Human stem cell-based models to study synaptic dysfunction and cognition in schizophrenia: A narrative review},
author = {Stephanie Santarriaga and Kaia Gerlovin and Yasmine Layadi and Rakesh Karmacharya},
doi = {10.1016/j.schres.2023.02.029},
issn = {1573-2509},
year  = {2023},
date = {2023-03-01},
journal = {Schizophr Res},
abstract = {Cognitive impairment is the strongest predictor of functional outcomes in schizophrenia and is hypothesized to result from synaptic dysfunction. However, targeting synaptic plasticity and cognitive deficits in patients remains a significant clinical challenge. A comprehensive understanding of synaptic plasticity and the molecular basis of learning and memory in a disease context can provide specific targets for the development of novel therapeutics targeting cognitive impairments in schizophrenia. Here, we describe the role of synaptic plasticity in cognition, summarize evidence for synaptic dysfunction in schizophrenia and demonstrate the use of patient derived induced-pluripotent stem cells for studying synaptic plasticity in vitro. Lastly, we discuss current advances and future technologies for bridging basic science research of synaptic dysfunction with clinical and translational research that can be used to predict treatment response and develop novel therapeutics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37181927,
title = {Chronotype Polygenic Score and the Timing and Quality of Workplace Cafeteria Purchases: Secondary Analysis of the ChooseWell 365 Randomized Controlled Trial},
author = {Hassan S Dashti and Kaitlyn Alimenti and Douglas E Levy and Marie-France Hivert and Jessica L McCurley and Richa Saxena and Anne N Thorndike},
doi = {10.1016/j.cdnut.2023.100048},
issn = {2475-2991},
year  = {2023},
date = {2023-03-01},
journal = {Curr Dev Nutr},
volume = {7},
number = {3},
pages = {100048},
abstract = {BACKGROUND: Studies on the link between chronotype (i.e., propensity for morning or evening preference) and dietary intake have relied on self-reported data, estimating consumption, and chronotype from questionnaires.nnOBJECTIVES: This study examined the associations between genetically proxied evening chronotype, objectively estimated workplace dietary choices, and the effectiveness of a behavioral intervention in hospital employees enrolled in the ChooseWell 365 study.nnMETHODS: ChooseWell 365 was a randomized trial of a 12-mo automated, personalized intervention to prevent weight gain and improve diet. Cafeteria sales data were used to measure the timing and healthfulness of workplace food purchases of employees during the 12-mo-long baseline, intervention, and postintervention follow-up periods. A genome-wide polygenic score for evening chronotype was calculated for all participants and the population was divided into quartiles; the highest quartile indicated the most evening chronotype. Associations between polygenic score quartiles and workplace purchases at baseline, 12 mo, and 24 mo and changes from baseline at 12 and 24 mo were tested using adjusted multivariable linear regression models.nnRESULTS: At baseline, the highest chronotype quartile was associated with self-reported breakfast skipping. Over the 24-mo study, the highest quartile was associated with later timing of the first workplace purchase, but not with the healthfulness of purchases. There were no differences by the chronotype quartile in the effectiveness of the ChooseWell 365 intervention in improving employees' healthy food choices at work.nnCONCLUSIONS: A chronotype polygenic score was associated with breakfast skipping and later workplace mealtimes of hospital employees, but not with the nutritional quality of objectively measured workplace food purchases. In addition, employees across the chronotype spectrum benefited from the workplace healthy eating intervention.This trial was registered at clinicaltrials.gov as NCT02660086 (https://clinicaltrials.gov/ct2/show/NCT02660086?cond=NCT02660086&draw=2&rank=1).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36993194,
title = {Mapping the dynamic genetic regulatory architecture of  genes at single-cell resolution},
author = {Joyce B Kang and Amber Z Shen and Saori Sakaue and Yang Luo and Saisriram Gurajala and Aparna Nathan and Laurie Rumker and Vitor R C Aguiar and Cristian Valencia and Kaitlyn Lagattuta and Fan Zhang and Anna Helena Jonsson and Seyhan Yazar and Jose Alquicira-Hernandez and Hamed Khalili and Ashwin N Ananthakrishnan and Karthik Jagadeesh and Kushal Dey and  and Mark J Daly and Ramnik J Xavier and Laura T Donlin and Jennifer H Anolik and Joseph E Powell and Deepak A Rao and Michael B Brenner and Maria Gutierrez-Arcelus and Soumya Raychaudhuri},
doi = {10.1101/2023.03.14.23287257},
year  = {2023},
date = {2023-03-01},
journal = {medRxiv},
abstract = {The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation in  genes has been extensively documented, regulatory genetic variation modulating  expression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classical  genes across 1,073 individuals and 1,131,414 single cells from three tissues, using personalized reference genomes to mitigate technical confounding. We identified cell-type-specific  eQTLs for every classical  gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type.  genes exhibit particularly cell-state-dependent effects within myeloid, B, and T cells. Dynamic  regulation may underlie important interindividual variability in immune responses.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37034593,
title = {Advancing Understanding of Inequities in Rare Disease Genomics},
author = {Jillian G Serrano and Melanie O'Leary and Grace VanNoy and Ingrid A Holm and Yarden S Fraiman and Heidi L Rehm and Anne O'Donnell-Luria and Monica H Wojcik},
doi = {10.1101/2023.03.28.23286936},
year  = {2023},
date = {2023-03-01},
journal = {medRxiv},
abstract = {PURPOSE: Advances in genomic research have led to the diagnosis of rare, early-onset diseases for thousands of individuals. Unfortunately, the benefits of advanced genetic diagnostic technology are not distributed equitably among the population, as has been seen in many other healthcare contexts. Even quantifying and describing inequities in genetic diagnostic yield is challenging due to variation in referrals to clinical genetics practices and other barriers to clinical genetic testing.nnMETHODS: The Rare Genomes Project (RGP) at the Broad Institute of MIT and Harvard offers research genome sequencing to individuals with rare disease who remain genetically undiagnosed through direct interaction with the individual or family. This presents an opportunity for diagnosis beyond the clinical context, thus eliminating many barriers to access.nnFINDINGS: An initial goal of RGP was to equalize access to genomic sequencing by decoupling testing access from proximity to a major medical center and physician referral. However, our study participants are overwhelmingly non-disadvantaged, as evidenced by their access to specialist care and genetic testing prior to RGP enrollment, and are also predominantly white.nnIMPLICATIONS: We therefore describe our novel initiative to diversify RGP enrollment in order to advance equity in rare disease genetic diagnosis and research. In addition to the moral imperative of medical equity, this is also critical in order to fully understand the genomic underpinnings of rare disease. We utilize a mixed methods approach to understand the priorities and values of underrepresented communities, existing disparities, and the obstacles to addressing them: all of which is necessary to promote equity in future genomic medicine initiatives.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36538912,
title = {Cardiometabolic profiles in children and adults with overweight and obesity and down syndrome},
author = {Nicolas M Oreskovic and Nicole T Baumer and Chiara Di Camillo and Michelle Cornachia and Catherine Franklin and Sarah J Hart and Priya S Kishnani and Andrew McCormick and Anna L Milliken and Vasiliki Patsiogiannis and Katherine G Pawlowski and Stephanie L Santoro and Sabrina Sargado and Vittorio Scoppola and Amy Torres and Diletta Valentini and Kishore Vellody and Alberto Villani and Brian G Skotko},
doi = {10.1002/ajmg.a.63088},
issn = {1552-4833},
year  = {2023},
date = {2023-03-01},
journal = {Am J Med Genet A},
volume = {191},
number = {3},
pages = {813--822},
abstract = {Individuals with Down syndrome (DS) are at increased risk for being overweight/obese, but the associated cardiometabolic risk (CR) is not clear. Cross-sectional anthropometric and clinical laboratory data from a multi-site, international cohort of individuals with DS were analyzed to determine cardiometabolic risk by reporting observed distributions of cardiometabolic biomarkers in overweight/obese individuals with DS throughout the lifespan. Descriptive statistics and regression analyses by age categories determined the distributive percentiles for cardiometabolic biomarkers and tested for adiposity as a predictor of CR. Across seven DS clinics, data were collected on 240 patients between the ages of 3 and 63 years, with one quarter overweight and three quarters obese among children and nearly all adults being obese. In children and adults, most cardiometabolic biomarker profiles showed distributive values within normal ranges. Blood lipids were positively associated with body mass index (BMI) in children (high density lipid-cholesterol, p = 0.01; low density lipid-cholesterol, p = 0.02). Levels of hs-CRP were elevated in both children and adults, with BMI positively associated with hs-CRP in adults with DS (p = 0.04). Liver enzyme values were positively associated with BMI in children and adults. The data suggest that in contrast to the general population, in individuals with Down syndrome, being overweight and obese does not appear to confer a significantly increased risk for cardiometabolic disease by biomarker profile. Individuals with DS who are overweight/obese appear to have unique cardiometabolic profiles unrelated to adiposity, notable for increased hs-CRP and normal HA1c levels.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36549913,
title = {Association of Soluble ST2 With Functional Outcome, Perihematomal Edema, and Immune Response After Intraparenchymal Hemorrhage},
author = {Matthew B Bevers and Caroline Booraem and Karen Li and Anirudh Sreekrishnan and Cristina Sastre and Guido J Falcone and Kevin Navin Sheth and Lauren H Sansing and W Taylor Kimberly},
doi = {10.1212/WNL.0000000000206764},
issn = {1526-632X},
year  = {2023},
date = {2023-03-01},
journal = {Neurology},
volume = {100},
number = {13},
pages = {e1329--e1338},
abstract = {BACKGROUND AND OBJECTIVES: Perihematomal edema (PHE) contributes to poor outcome after deep intraparenchymal hemorrhage (IPH), which is characterized by neuroinflammation and an influx of peripherally derived innate immune cells. We previously identified soluble ST2 (sST2) as a candidate for immune-mediated secondary brain injury. Leveraging prospectively collected cohorts from 2 centers, we sought to determine whether sST2 was associated with functional outcome, PHE, and the immune response following IPH.nnMETHODS: Patients with deep IPH were enrolled within 36 hours of ictus, and blood was collected for sST2 and immune cell measurement. Hematoma volume and PHE were measured on serial CT scans. Good outcome was defined as a modified Rankin Scale score of 0-3 at 90 days. Linear mixed-effects models were used to analyze the relationship between sST2 and PHE over time. Flow cytometry was used to identify shifts in immune cell populations associated with sST2. Immunohistochemistry of human brain tissue was used to identify ST2-expressing cells in the perihematomal region.nnRESULTS: The 55 included patients had a median admission Glasgow Coma Scale score of 14 (interquartile range [IQR] 9-15), an intracerebral hemorrhage (ICH) score of 1 (IQR 1-2), and a hematoma volume of 8.6 mL (IQR 3.4-13.8 mL). Receiver operating curve analysis found the sST2 level to be predictive of poor outcome with an area under the curve of 0.763 (95% CI 0.632-0.894) and Youden optimum cut point of 61.8 ng/mL ( < 0.001). sST2 remained an independent predictor after adjustment for ICH score (adjusted odds ratio 2.53, 95% CI 1.03-6.19,  = 0.042). Measurement of PHE found those patients with high sST2 to have greater edema volume over time (β = 1.07, 95% CI 0.51-1.63,  < 0.001). High sST2 was associated with a shift toward an innate peripheral immune response (monocytes and natural killer cells; 68.6% ± 5.1% vs 47.5% ± 4.0%;  = 0.003).nnDISCUSSION: Our findings demonstrate that elevated sST2 links the peripheral innate immune response to PHE volume and outcome after IPH. This knowledge is relevant to future studies that seek to identify patients with IPH at highest risk for immune-mediated injury or limit injury through targeted interventions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36809767,
title = {Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia},
author = {Elisabetta Morini and Anil Chekuri and Emily M Logan and Jessica M Bolduc and Emily G Kirchner and Monica Salani and Aram J Krauson and Jana Narasimhan and Vijayalakshmi Gabbeta and Shivani Grover and Amal Dakka and Anna Mollin and Stephen P Jung and Xin Zhao and Nanjing Zhang and Sophie Zhang and Michael Arnold and Matthew G Woll and Nikolai A Naryshkin and Marla Weetall and Susan A Slaugenhaupt},
doi = {10.1016/j.ajhg.2023.01.019},
issn = {1537-6605},
year  = {2023},
date = {2023-03-01},
journal = {Am J Hum Genet},
volume = {110},
number = {3},
pages = {531--547},
abstract = {Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 production in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in individuals with FD. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound PTC258 efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1 increases full-length ELP1 transcript in a dose-dependent manner and leads to a 2-fold increase in functional ELP1 in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37078667,
title = {Wrestling with Social and Behavioral Genomics: Risks, Potential Benefits, and Ethical Responsibility},
author = {Michelle N Meyer and Paul S Appelbaum and Daniel J Benjamin and Shawneequa L Callier and Nathaniel Comfort and Dalton Conley and Jeremy Freese and Nanibaa' A Garrison and Evelynn M Hammonds and K Paige Harden and Sandra Soo-Jin Lee and Alicia R Martin and Daphne Oluwaseun Martschenko and Benjamin M Neale and Rohan H C Palmer and James Tabery and Eric Turkheimer and Patrick Turley and Erik Parens},
doi = {10.1002/hast.1477},
issn = {1552-146X},
year  = {2023},
date = {2023-03-01},
journal = {Hastings Cent Rep},
volume = {53 Suppl 1},
number = {Suppl 1},
pages = {S2--S49},
abstract = {In this consensus report by a diverse group of academics who conduct and/or are concerned about social and behavioral genomics (SBG) research, the authors recount the often-ugly history of scientific attempts to understand the genetic contributions to human behaviors and social outcomes. They then describe what the current science-including genomewide association studies and polygenic indexes-can and cannot tell us, as well as its risks and potential benefits. They conclude with a discussion of responsible behavior in the context of SBG research. SBG research that compares individuals within a group according to a "sensitive" phenotype requires extra attention to responsible conduct and to responsible communication about the research and its findings. SBG research (1) on sensitive phenotypes that (2) compares two or more groups defined by (a) race, (b) ethnicity, or (c) genetic ancestry (where genetic ancestry could easily be misunderstood as race or ethnicity) requires a compelling justification to be conducted, funded, or published. All authors agree that this justification at least requires a convincing argument that a study's design could yield scientifically valid results; some authors would additionally require the study to have a socially favorable risk-benefit profile.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36779498,
title = {Functional Characterization of Six  (OATP1B1) Variants Observed in Finnish Individuals with a Psychotic Disorder},
author = {Katja Häkkinen and Wilma Kiander and Heidi Kidron and Markku Lähteenvuo and Lea Urpa and Jonne Lintunen and Kati-Sisko Vellonen and Seppo Auriola and Minna Holm and Kaisla Lahdensuo and Olli Kampman and Erkki Isometsä and Tuula Kieseppä and Jouko Lönnqvist and Jaana Suvisaari and Jarmo Hietala and Jari Tiihonen and Aarno Palotie and Ari V Ahola-Olli and Mikko Niemi},
doi = {10.1021/acs.molpharmaceut.2c00715},
issn = {1543-8392},
year  = {2023},
date = {2023-03-01},
journal = {Mol Pharm},
volume = {20},
number = {3},
pages = {1500--1508},
abstract = {Variants in the  (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare  single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime.  SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2',7'-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of  were identified in the study population, located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants,  c.629G>T (p.210G>V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants,  c.629G>T (p.210G>V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of  c.629G>T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36477409,
title = {Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project},
author = {Eleanor G Seaby and N Simon Thomas and Amy Webb and Helen Brittain and Ana Lisa Taylor Tavares and  and Diana Baralle and Heidi L Rehm and Anne O'Donnell-Luria and Sarah Ennis},
doi = {10.1007/s00439-022-02509-x},
issn = {1432-1203},
year  = {2023},
date = {2023-03-01},
journal = {Hum Genet},
volume = {142},
number = {3},
pages = {351--362},
abstract = {BACKGROUND: Genome sequencing was first offered clinically in the UK through the 100,000 Genomes Project (100KGP). Analysis was restricted to predefined gene panels associated with the patient's phenotype. However, panels rely on clearly characterised phenotypes and risk missing diagnoses outside of the panel(s) applied. We propose a complementary method to rapidly identify pathogenic variants, including those missed by 100KGP methods.nnMETHODS: The Loss-of-function Observed/Expected Upper-bound Fraction (LOEUF) score quantifies gene constraint, with low scores correlated with haploinsufficiency. We applied DeNovoLOEUF, a filtering strategy to sequencing data from 13,949 rare disease trios in the 100KGP, by filtering for rare, de novo, loss-of-function variants in disease genes with a LOEUF score < 0.2. We compared our findings with the corresponding patient's diagnostic reports.nnRESULTS: 324/332 (98%) of the variants identified using DeNovoLOEUF were diagnostic or partially diagnostic (whereby the variant was responsible for some of the phenotype). We identified 39 diagnoses that were "missed" by 100KGP standard analyses, which are now being returned to patients.nnCONCLUSION: We have demonstrated a highly specific and rapid method with a 98% positive predictive value that has good concordance with standard analysis, low false-positive rate, and can identify additional diagnoses. Globally, as more patients are being offered genome sequencing, we anticipate that DeNovoLOEUF will rapidly identify new diagnoses and facilitate iterative analyses when new disease genes are discovered.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36162806,
title = {Disentangling the influences of parental genetics on offspring's cognition, education, and psychopathology via genetic and phenotypic pathways},
author = {Luiza K Axelrud and Maurício S Hoffmann and Daniel E Vosberg and Marcos Santoro and Pedro M Pan and Ary Gadelha and Sintia I Belangero and Euripedes C Miguel and Jean Shin and Anita Thapar and Jordan W Smoller and Zdenka Pausova and Luis A Rohde and Matthew C Keller and Tomáš Paus and Giovanni A Salum},
doi = {10.1111/jcpp.13708},
issn = {1469-7610},
year  = {2023},
date = {2023-03-01},
journal = {J Child Psychol Psychiatry},
volume = {64},
number = {3},
pages = {408--416},
abstract = {BACKGROUND: Specific pathways of intergenerational transmission of behavioral traits remain unclear. Here, we aim to investigate how parental genetics influence offspring cognition, educational attainment, and psychopathology in youth.nnMETHODS: Participants for the discovery sample were 2,189 offspring (aged 6-14 years), 1898 mothers and 1,017 fathers who underwent genotyping, psychiatric, and cognitive assessments. We calculated polygenic scores (PGS) for cognition, educational attainment, attention-deficit hyperactivity disorder (ADHD), and schizophrenia for the trios. Phenotypes studied included educational and cognitive measures, ADHD and psychotic symptoms. We used a stepwise approach and multiple mediation models to analyze the effect of parental PGS on offspring traits via offspring PGS and parental phenotype. Significant results were replicated in a sample of 1,029 adolescents, 363 mothers, and 307 fathers.nnRESULTS: Maternal and paternal PGS for cognition influenced offspring general intelligence and executive function via offspring PGS (genetic pathway) and parental education (phenotypic pathway). Similar results were found for parental PGS for educational attainment and offspring reading and writing skills. These pathways fully explained associations between parental PGS and offspring phenotypes, without residual direct association. Associations with maternal, but not paternal, PGS were replicated. No associations were found between parental PGS for psychopathology and offspring specific symptoms.nnCONCLUSIONS: Our findings indicate that parental genetics influences offspring cognition and educational attainment by genetic and phenotypic pathways, suggesting the expression of parental phenotypes partially explain the association between parental genetic risk and offspring outcomes. Multiple mediations might represent an effective approach to disentangle distinct pathways for intergenerational transmission of behavioral traits.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36724785,
title = {Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly},
author = {Margaux Serey-Gaut and Marisol Cortes and Periklis Makrythanasis and Mohnish Suri and Alexander M R Taylor and Jennifer A Sullivan and Ayat N Asleh and Jaba Mitra and Mohamad A Dar and Amy McNamara and Vandana Shashi and Sarah Dugan and Xiaofei Song and Jill A Rosenfeld and Christelle Cabrol and Justyna Iwaszkiewicz and Vincent Zoete and Davut Pehlivan and Zeynep Coban Akdemir and Elizabeth R Roeder and Rebecca Okashah Littlejohn and Harpreet K Dibra and Philip J Byrd and Grant S Stewart and Bilgen B Geckinli and Jennifer Posey and Rachel Westman and Chelsy Jungbluth and Jacqueline Eason and Rani Sachdev and Carey-Anne Evans and Gabrielle Lemire and Grace E VanNoy and Anne O'Donnell-Luria and Frédéric Tran Mau-Them and Aurélien Juven and Juliette Piard and Cheng Yee Nixon and Ying Zhu and Taekjip Ha and Michael F Buckley and Christel Thauvin and George K Essien Umanah and Lionel Van Maldergem and James R Lupski and Tony Roscioli and Valina L Dawson and Ted M Dawson and Stylianos E Antonarakis},
doi = {10.1016/j.ajhg.2023.01.006},
issn = {1537-6605},
year  = {2023},
date = {2023-03-01},
journal = {Am J Hum Genet},
volume = {110},
number = {3},
pages = {499--515},
abstract = {Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36996212,
title = {Analysis of genetic dominance in the UK Biobank},
author = {Duncan S Palmer and Wei Zhou and Liam Abbott and Emilie M Wigdor and Nikolas Baya and Claire Churchhouse and Cotton Seed and Tim Poterba and Daniel King and Masahiro Kanai and Alex Bloemendal and Benjamin M Neale},
doi = {10.1126/science.abn8455},
issn = {1095-9203},
year  = {2023},
date = {2023-03-01},
journal = {Science},
volume = {379},
number = {6639},
pages = {1341--1348},
abstract = {Classical statistical genetics theory defines dominance as any deviation from a purely additive, or dosage, effect of a genotype on a trait, which is known as the dominance deviation. Dominance is well documented in plant and animal breeding. Outside of rare monogenic traits, however, evidence in humans is limited. We systematically examined common genetic variation across 1060 traits in a large population cohort (UK Biobank,  = 361,194 samples analyzed) for evidence of dominance effects. We then developed a computationally efficient method to rapidly assess the aggregate contribution of dominance deviations to heritability. Lastly, observing that dominance associations are inherently less correlated between sites at a genomic locus than their additive counterparts, we explored whether they may be leveraged to identify causal variants more confidently.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36621119,
title = {Cerebral arteriopathy and ischemic stroke in a pediatric MYH11 patient},
author = {Ashrita Raghuram and Sebastian Sanchez and Yongjun Lu and Meredith Hickerson and Maria Belen Solis Mayorga and Javier M Romero and Satsuki Matsumoto and Patricia L Musolino and Edgar A Samaniego},
doi = {10.1016/j.jstrokecerebrovasdis.2022.106938},
issn = {1532-8511},
year  = {2023},
date = {2023-03-01},
journal = {J Stroke Cerebrovasc Dis},
volume = {32},
number = {3},
pages = {106938},
abstract = {OBJECTIVES: Mutations in the MYH11 gene result in smooth muscle cell dysfunction and are associated with familial thoracic aortic aneurysms and dissection. We describe a pediatric patient with a stroke and a pathogenic MYH11 IVS32G>A mutation, and a phenotype similar to ACTA2.nnMETHODS: A proband girl with an acute ischemic stroke underwent genetic analysis and 7T high-resolution MRI.nnRESULTS: A 12-year-old girl presented with a right middle cerebral artery occlusion. She received thrombolysis and underwent mechanical thrombectomy. An extensive stroke work-up was negative. A three-generation pedigree showed a splice site mutation of MYH11 IVS32G>A of the proband and three more family members. A 7T-MRI showed "broomstick-like" straightening of distal arterial segments, a V-shaped anterior corpus callosum and a post-stroke cystic area of encephalomalacia. This vascular appearance and parenchymal abnormalities typically present in patients with an ACTA2 phenotype. 7T-MRI also demonstrated thickening of the right middle cerebral arterial wall.nnDISCUSSION: This case suggests that MYH11 patients may have a similar angiographic and brain parenchymal phenotype to patients with ACTA2 mutations. This is the first report of arterial wall thickening in a MYH11 stroke patient using 7T-MRI. Patients with MYH11 mutations may display a focal cerebral steno-occlusive arteriopathy that may lead to stroke.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36945502,
title = {Advanced variant classification framework reduces the false positive rate of predicted loss of function (pLoF) variants in population sequencing data},
author = {Moriel Singer-Berk and Sanna Gudmundsson and Samantha Baxter and Eleanor G Seaby and Eleina England and Jordan C Wood and Rachel G Son and Nicholas A Watts and Konrad J Karczewski and Steven M Harrison and Daniel G MacArthur and Heidi L Rehm and Anne O'Donnell-Luria},
doi = {10.1101/2023.03.08.23286955},
year  = {2023},
date = {2023-03-01},
journal = {medRxiv},
abstract = {Predicted loss of function (pLoF) variants are highly deleterious and play an important role in disease biology, but many of these variants may not actually result in loss-of-function. Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines's PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 autosomal recessive disease-genes from the Genome Aggregation Database (gnomAD, v2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in low per-base expression (pext) score regions, or the presence of cryptic splice rescues. Variants predicted to be potential artifacts or to evade LoF were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of LoF evading variants assessed, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines, and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36756894,
title = {Genetic Risk Score Improves Risk Stratification for Anticoagulation-Related Intracerebral Hemorrhage},
author = {Ernst Mayerhofer and Livia Parodi and Savvina Prapiadou and Rainer Malik and Jonathan Rosand and Marios K Georgakis and Christopher D Anderson},
doi = {10.1161/STROKEAHA.122.041764},
issn = {1524-4628},
year  = {2023},
date = {2023-03-01},
journal = {Stroke},
volume = {54},
number = {3},
pages = {791--799},
abstract = {BACKGROUND: Intracerebral hemorrhage (ICH) is the most devastating adverse outcome for patients on anticoagulants. Clinical risk scores that quantify bleeding risk can guide decision-making in situations when indication or duration for anticoagulation is uncertain. We investigated whether integration of a genetic risk score into an existing risk factor-based CRS could improve risk stratification for anticoagulation-related ICH.nnMETHODS: We constructed 153 genetic risk scores from genome-wide association data of 1545 ICH cases and 1481 controls and validated them in 431 ICH cases and 431 matched controls from the population-based UK Biobank. The score that explained the largest variance in ICH risk was selected and tested for prediction of incident ICH in an independent cohort of 5530 anticoagulant users. A CRS for major anticoagulation-related hemorrhage, based on 8/9 components of the HAS-BLED score, was compared with a combined clinical and genetic risk score incorporating an additional point for high genetic risk for ICH.nnRESULTS: Among anticoagulated individuals, 94 ICH occurred over a mean follow-up of 11.9 years. Compared with the lowest genetic risk score tertile, being in the highest tertile was associated with a two-fold increased risk for incident ICH (hazard ratio, 2.08 [95% CI, 1.22-3.56]). Although the CRS predicted incident ICH with a hazard ratio of 1.24 per 1-point increase (95% CI [1.01-1.53]), adding a point for high genetic ICH risk led to a stronger association (hazard ratio of 1.33 per 1-point increase [95% CI, 1.11-1.59]) with improved risk stratification (C index 0.57 versus 0.53) and maintained calibration (integrated calibration index 0.001 for both). The new clinical and genetic risk score showed 19% improvement in high-risk classification among individuals with ICH and a net reclassification improvement of 0.10.nnCONCLUSIONS: Among anticoagulant users, a prediction score incorporating genomic information is superior to a clinical risk score alone for ICH risk stratification and could serve in clinical decision-making.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36945419,
title = {PAM-Flexible Genome Editing with an Engineered Chimeric Cas9},
author = {Sabrina Koseki and Lauren Hong and Vivian Yudistyra and Teodora Stan and Emma Tysinger and Rachel Silverstein and Christian Kramme and Nadia Amrani and Natasha Savic and Martin Pacesa and Tom S Rodriguez and Manvitha Ponnapati and Joseph Jacobson and George Church and Ray Truant and Martin Jinek and Benjamin Kleinstiver and Erik Sontheimer and Pranam Chatterjee},
doi = {10.21203/rs.3.rs-2625838/v1},
year  = {2023},
date = {2023-03-01},
journal = {Res Sq},
abstract = {CRISPR enzymes require a defined protospacer adjacent motif (PAM) flanking a guide RNA-programmed target site, limiting their sequence accessibility for robust genome editing applications. In this study, we recombine the PAM-interacting domain of SpRY, a broad-targeting Cas9 possessing an NRN > NYN PAM preference, with the N-terminus of Sc++, a Cas9 with simultaneously broad, efficient, and accurate NNG editing capabilities, to generate a chimeric enzyme with highly flexible PAM preference: SpRYc. We demonstrate that SpRYc leverages properties of both enzymes to specifically edit diverse NNN PAMs and disease-related loci for potential therapeutic applications. In total, the unique approaches to generate SpRYc, coupled with its robust flexibility, highlight the power of integrative protein design for Cas9 engineering and motivate downstream editing applications that require precise genomic positioning.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37034701,
title = {A gene pathogenicity tool 'GenePy' identifies missed biallelic diagnoses in the 100,000 Genomes Project},
author = {Eleanor G Seaby and Gary Leggatt and Guo Cheng and N Simon Thomas and James J Ashton and Imogen Stafford and  and Diana Baralle and Heidi L Rehm and Anne O'Donnell-Luria and Sarah Ennis},
doi = {10.1101/2023.03.21.23287545},
year  = {2023},
date = {2023-03-01},
journal = {medRxiv},
abstract = {The 100,000 Genomes Project (100KGP) diagnosed a quarter of recruited affected participants, but 26% of diagnoses were in genes not on the chosen gene panel(s); with many being  variants of high impact. However, assessing biallelic variants without a gene panel is challenging, due to the number of variants requiring scrutiny. We sought to identify potential missed biallelic diagnoses independent of the gene panel applied using GenePy - a whole gene pathogenicity metric. GenePy scores all variants called in a given individual, incorporating allele frequency, zygosity, and a user-defined deleterious metric (CADD v1.6 applied herein). GenePy then combines all variant scores for individual genes, generating an aggregate score per gene, per participant. We calculated GenePy scores for 2862 recessive disease genes in 78,216 individuals in 100KGP. For each gene, we ranked participant GenePy scores for that gene, and scrutinised affected individuals without a diagnosis whose scores ranked amongst the top-5 for each gene. We assessed these participants' phenotypes for overlap with the disease gene associated phenotype for which they were highly ranked. Where phenotypes overlapped, we extracted rare variants in the gene of interest and applied phase, ClinVar and ACMG classification looking for putative causal biallelic variants. 3184 affected individuals without a molecular diagnosis had a top-5 ranked GenePy gene score and 682/3184 (21%) had phenotypes overlapping with one of the top-ranking genes. After removing 13 withdrawn participants, in 122/669 (18%) of the phenotype-matched cases, we identified a putative missed diagnosis in a top-ranked gene supported by phasing, ClinVar and ACMG classification. A further 334/669 (50%) of cases have a possible missed diagnosis but require functional validation. Applying GenePy at scale has identified potential diagnoses for 456/3183 (14%) of undiagnosed participants who had a top-5 ranked GenePy score in a recessive disease gene, whilst adding only 1.2 additional variants (per individual) for assessment.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36373825,
title = {Plasma Metabolites Link Dietary Patterns to Stroke Risk},
author = {Varun M Bhave and Zsuzsanna Ament and Amit Patki and Yan Gao and Naruchorn Kijpaisalratana and Boyi Guo and Ninad S Chaudhary and Ana-Lucia Garcia Guarniz and Robert Gerszten and Adolfo Correa and Mary Cushman and Suzanne Judd and M Ryan Irvin and W Taylor Kimberly},
doi = {10.1002/ana.26552},
issn = {1531-8249},
year  = {2023},
date = {2023-03-01},
journal = {Ann Neurol},
volume = {93},
number = {3},
pages = {500--510},
abstract = {OBJECTIVE: While dietary intake is linked to stroke risk, surrogate markers that could inform personalized dietary interventions are lacking. We identified metabolites associated with diet patterns and incident stroke in a nested cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.nnMETHODS: Levels of 162 metabolites were measured in baseline plasma from stroke cases (n = 1,198) and random controls (n = 904). We examined associations between metabolites and a plant-based diet pattern previously linked to reduced stroke risk in REGARDS. Secondary analyses included 3 additional stroke-associated diet patterns: a Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Southern diet. Metabolites were tested using Cox proportional hazards models with incident stroke as the outcome. Replication was performed in the Jackson Heart Study (JHS). Inverse odds ratio-weighted mediation was used to determine whether metabolites mediated the association between a plant-based diet and stroke risk.nnRESULTS: Metabolites associated with a plant-based diet included the gut metabolite indole-3-propionic acid (β = 0.23, 95% confidence interval [CI] [0.14, 0.33], p = 1.14 × 10 ), guanosine (β = -0.13, 95% CI [-0.19, -0.07], p = 6.48 × 10 ), gluconic acid (β = -0.11, 95% CI [-0.18, -0.04], p = 2.06 × 10 ), and C7 carnitine (β = -0.16, 95% CI [-0.24, -0.09], p = 4.14 × 10 ). All of these metabolites were associated with both additional diet patterns and altered stroke risk. Mediation analyses identified guanosine (32.6% mediation, p = 1.51 × 10 ), gluconic acid (35.7%, p = 2.28 × 10 ), and C7 carnitine (26.2%, p = 1.88 × 10 ) as mediators linking a plant-based diet to reduced stroke risk.nnINTERPRETATION: A subset of diet-related metabolites are associated with risk of stroke. These metabolites could serve as surrogate markers that inform dietary interventions. ANN NEUROL 2023;93:500-510.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36328855,
title = {Derivation and Validation of a Brief Emergency Department-Based Prediction Tool for Posttraumatic Stress After Motor Vehicle Collision},
author = {Christopher W Jones and Xinming An and Yinyao Ji and Mochuan Liu and Donglin Zeng and Stacey L House and Francesca L Beaudoin and Jennifer S Stevens and Thomas C Neylan and Gari D Clifford and Tanja Jovanovic and Sarah D Linnstaedt and Laura T Germine and Kenneth A Bollen and Scott L Rauch and John P Haran and Alan B Storrow and Christopher Lewandowski and Paul I Musey and Phyllis L Hendry and Sophia Sheikh and Brittany E Punches and Michael S Lyons and Michael C Kurz and Robert A Swor and Meghan E McGrath and Lauren A Hudak and Jose L Pascual and Mark J Seamon and Elizabeth M Datner and Erica Harris and Anna M Chang and Claire Pearson and David A Peak and Roland C Merchant and Robert M Domeier and Niels K Rathlev and Brian J O'Neil and Paulina Sergot and Leon D Sanchez and Steven E Bruce and Mark W Miller and Robert H Pietrzak and Jutta Joormann and Deanna M Barch and Diego A Pizzagalli and John F Sheridan and Jordan W Smoller and Steven E Harte and James M Elliott and Karestan C Koenen and Kerry J Ressler and Ronald C Kessler and Samuel A McLean},
doi = {10.1016/j.annemergmed.2022.08.011},
issn = {1097-6760},
year  = {2023},
date = {2023-03-01},
journal = {Ann Emerg Med},
volume = {81},
number = {3},
pages = {249--261},
abstract = {STUDY OBJECTIVE: To derive and initially validate a brief bedside clinical decision support tool that identifies emergency department (ED) patients at high risk of substantial, persistent posttraumatic stress symptoms after a motor vehicle collision.nnMETHODS: Derivation (n=1,282, 19 ED sites) and validation (n=282, 11 separate ED sites) data were obtained from adults prospectively enrolled in the Advancing Understanding of RecOvery afteR traumA study who were discharged from the ED after motor vehicle collision-related trauma. The primary outcome was substantial posttraumatic stress symptoms at 3 months (Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-5 ≥38). Logistic regression derivation models were evaluated for discriminative ability using the area under the curve and the accuracy of predicted risk probabilities (Brier score). Candidate posttraumatic stress predictors assessed in these models (n=265) spanned a range of sociodemographic, baseline health, peritraumatic, and mechanistic domains. The final model selection was based on performance and ease of administration.nnRESULTS: Significant 3-month posttraumatic stress symptoms were common in the derivation (27%) and validation (26%) cohort. The area under the curve and Brier score of the final 8-question tool were 0.82 and 0.14 in the derivation cohort and 0.76 and 0.17 in the validation cohort.nnCONCLUSION: This simple 8-question tool demonstrates promise to risk-stratify individuals with substantial posttraumatic stress symptoms who are discharged to home after a motor vehicle collision. Both external validation of this instrument, and work to further develop more accurate tools, are needed. Such tools might benefit public health by enabling the conduct of preventive intervention trials and assisting the growing number of EDs that provide services to trauma survivors aimed at promoting psychological recovery.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36868203,
title = {2022 Curt Stern Award: Advancing genomic medicine through collaboration and data sharing},
author = {Heidi L Rehm},
doi = {10.1016/j.ajhg.2023.01.013},
issn = {1537-6605},
year  = {2023},
date = {2023-03-01},
journal = {Am J Hum Genet},
volume = {110},
number = {3},
pages = {410--413},
abstract = {This article is based on the address given by the author at the 2022 meeting of The American Society of Human Genetics (ASHG) in Los Angeles, CA. The video of the original address can be found at the ASHG website.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36791225,
title = {Systolic Blood Pressure and Cardiovascular Risk: Straightening the Evidence},
author = {Cian P McCarthy and Pradeep Natarajan},
doi = {10.1161/HYPERTENSIONAHA.123.20788},
issn = {1524-4563},
year  = {2023},
date = {2023-03-01},
journal = {Hypertension},
volume = {80},
number = {3},
pages = {577--579},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36493376,
title = {Healthcare experiences of patients with Down syndrome who are Black, African American, of African descent, or of mixed race},
author = {Kavita Krell and Albert Pless and Carie Michael and Amy Torres and Jeanhee Chung and Sandra Baker and Jasmine M Blake and Kelli Caughman and Sarah Cullen and Maureen Gallagher and Roxanne Hoke-Chandler and Julius Maina and Diana McLuckie and Kate O'Neill and Angeles Peña and Dina Royal and Michelle Slape and Noemi Alice Spinazzi and Carlos G Torres and Brian G Skotko},
doi = {10.1002/ajmg.a.63069},
issn = {1552-4833},
year  = {2023},
date = {2023-03-01},
journal = {Am J Med Genet A},
volume = {191},
number = {3},
pages = {742--752},
abstract = {Scant research has explored the healthcare experiences of people with Down syndrome (DS) in the United States who are Black, African American, of African descent, or of mixed race. The purpose of this study was to identify and describe the barriers and facilitators that such patients and their caregivers face when accessing healthcare. We gathered data in three ways: focus groups with caregivers, a national survey completed by caregivers, and in-depth interviews with primary care providers. Many caregivers and primary care physicians felt that patients with DS who are Black, African American, of African descent, or of mixed race receive a lower quality of medical care than their white counterparts with DS. Caregivers mentioned feeling tired of being reminded by the medical community about their race and wanting acknowledgment that raising a child with DS can be hard at times. Many felt that the medical community's conscious and unconscious racial biases do negatively impact the care of their loved ones with DS. Caregivers desired more race concordant medical providers or, when not possible, medical providers who are willing to learn more about DS and build trusted, longitudinal relationships. Primary care providers discussed the need for funded resources and support services to effectively care for their patients with DS.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36909456,
title = {Uncovering and mitigating bias in large, automated MRI analyses of brain development},
author = {Safia Elyounssi and Keiko Kunitoki and Jacqueline A Clauss and Eline Laurent and Kristina Kane and Dylan E Hughes and Casey E Hopkinson and Oren Bazer and Rachel Freed Sussman and Alysa E Doyle and Hang Lee and Brenden Tervo-Clemmens and Hamdi Eryilmaz and Randy L Gollub and Deanna M Barch and Theodore D Satterthwaite and Kevin F Dowling and Joshua L Roffman},
doi = {10.1101/2023.02.28.530498},
year  = {2023},
date = {2023-03-01},
journal = {bioRxiv},
abstract = {Large, population-based MRI studies of adolescents promise transformational insights into neurodevelopment and mental illness risk  . However, MRI studies of youth are especially susceptible to motion and other artifacts  . These artifacts may go undetected by automated quality control (QC) methods that are preferred in high-throughput imaging studies,  and can potentially introduce non-random noise into clinical association analyses. Here we demonstrate bias in structural MRI analyses of children due to inclusion of lower quality images, as identified through rigorous visual quality control of 11,263 T1 MRI scans obtained at age 9-10 through the Adolescent Brain Cognitive Development (ABCD) Study  . Compared to the best-rated images (44.9% of the sample), lower-quality images generally associated with decreased cortical thickness and increased cortical surface area measures (Cohen’s d 0.14-2.84). Variable image quality led to counterintuitive patterns in analyses that associated structural MRI and clinical measures, as inclusion of lower-quality scans altered apparent effect sizes in ways that increased risk for both false positives and negatives. Quality-related biases were partially mitigated by controlling for surface hole number, an automated index of topological complexity that differentiated lower-quality scans with good specificity at Baseline (0.81-0.93) and in 1,000 Year 2 scans (0.88-1.00). However, even among the highest-rated images, subtle topological errors occurred during image preprocessing, and their correction through manual edits significantly and reproducibly changed thickness measurements across much of the cortex (d 0.15-0.92). These findings demonstrate that inadequate QC of youth structural MRI scans can undermine advantages of large sample size to detect meaningful associations.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36723951,
title = {Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease},
author = {Jacqueline S Dron and Aniruddh P Patel and Yiyi Zhang and Sean J Jurgens and Dimitri J Maamari and Minxian Wang and Eric Boerwinkle and Alanna C Morrison and Paul S de Vries and Myriam Fornage and Lifang Hou and Donald M Lloyd-Jones and Bruce M Psaty and Russell P Tracy and Joshua C Bis and Ramachandran S Vasan and Daniel Levy and Nancy Heard-Costa and Stephen S Rich and Xiuqing Guo and Kent D Taylor and Richard A Gibbs and Jerome I Rotter and Cristen J Willer and Elizabeth C Oelsner and Andrew E Moran and Gina M Peloso and Pradeep Natarajan and Amit V Khera},
doi = {10.1001/jamacardio.2022.5271},
issn = {2380-6591},
year  = {2023},
date = {2023-03-01},
journal = {JAMA Cardiol},
volume = {8},
number = {3},
pages = {258--267},
abstract = {IMPORTANCE: Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.nnOBJECTIVE: To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.nnDESIGN, SETTING, AND PARTICIPANTS: This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.nnEXPOSURES: PTVs in APOB and PCSK9.nnMAIN OUTCOMES AND MEASURES: Estimated untreated LDL cholesterol levels and CHD.nnRESULTS: Among 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004).nnCONCLUSIONS AND RELEVANCE: Among 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36437642,
title = {Personal social networks of people with Down syndrome},
author = {Brian G Skotko and Kavita Krell and Kelsey Haugen and Amy Torres and Amber Nieves and Amar Dhand},
doi = {10.1002/ajmg.a.63059},
issn = {1552-4833},
year  = {2023},
date = {2023-03-01},
journal = {Am J Med Genet A},
volume = {191},
number = {3},
pages = {690--698},
abstract = {Studies in the neurotypical population have demonstrated that personal social networks can mitigate cognitive decline and the development of Alzheimer disease. To assess whether these benefits can also be extended to people with Down syndrome (DS), we studied whether and how personal networks can be measured in this population. We adapted a personal networks instrument previously created, validated, and implemented for the neurotypical population. We created two versions of the survey: one for participants with DS, ages 25 and older, and another for their study partners, who spent a minimum of 10 h/wk in a caregiver role. Participants with DS gave concordant data to those of study partners. Their personal networks included a median network size of 7.50, density 0.80, constraint 46.00, and effective size 3.07. Personal networks were composed of 50% kin, 80% who live within 15 miles, and 80% who eat a healthy diet. In this proof-of-principle study, we demonstrated that the personal networks of people with DS can be quantitatively analyzed, with no statistical difference between self-report and parent-proxy report. Future research efforts can now evaluate interventions to enhance personal networks for preventing Alzheimer disease in this population.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36538063,
title = {High-throughput genetic clustering of type 2 diabetes loci reveals heterogeneous mechanistic pathways of metabolic disease},
author = {Hyunkyung Kim and Kenneth E Westerman and Kirk Smith and Joshua Chiou and Joanne B Cole and Timothy Majarian and Marcin von Grotthuss and Soo Heon Kwak and Jaegil Kim and Josep M Mercader and Jose C Florez and Kyle Gaulton and Alisa K Manning and Miriam S Udler},
doi = {10.1007/s00125-022-05848-6},
issn = {1432-0428},
year  = {2023},
date = {2023-03-01},
journal = {Diabetologia},
volume = {66},
number = {3},
pages = {495--507},
abstract = {AIMS/HYPOTHESIS: Type 2 diabetes is highly polygenic and influenced by multiple biological pathways. Rapid expansion in the number of type 2 diabetes loci can be leveraged to identify such pathways.nnMETHODS: We developed a high-throughput pipeline to enable clustering of type 2 diabetes loci based on variant-trait associations. Our pipeline extracted summary statistics from genome-wide association studies (GWAS) for type 2 diabetes and related traits to generate a matrix of 323 variants × 64 trait associations and applied Bayesian non-negative matrix factorisation (bNMF) to identify genetic components of type 2 diabetes. Epigenomic enrichment analysis was performed in 28 cell types and single pancreatic cells. We generated cluster-specific polygenic scores and performed regression analysis in an independent cohort (N=25,419) to assess for clinical relevance.nnRESULTS: We identified ten clusters of genetic loci, recapturing the five from our prior analysis as well as novel clusters related to beta cell dysfunction, pronounced insulin secretion, and levels of alkaline phosphatase, lipoprotein A and sex hormone-binding globulin. Four clusters related to mechanisms of insulin deficiency, five to insulin resistance and one had an unclear mechanism. The clusters displayed tissue-specific epigenomic enrichment, notably with the two beta cell clusters differentially enriched in functional and stressed pancreatic beta cell states. Additionally, cluster-specific polygenic scores were differentially associated with patient clinical characteristics and outcomes. The pipeline was applied to coronary artery disease and chronic kidney disease, identifying multiple overlapping clusters with type 2 diabetes.nnCONCLUSIONS/INTERPRETATION: Our approach stratifies type 2 diabetes loci into physiologically interpretable genetic clusters associated with distinct tissues and clinical outcomes. The pipeline allows for efficient updating as additional GWAS become available and can be readily applied to other conditions, facilitating clinical translation of GWAS findings. Software to perform this clustering pipeline is freely available.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36519390,
title = {Genome-wide gene by environment study of time spent in daylight and chronotype identifies emerging genetic architecture underlying light sensitivity},
author = {Angus C Burns and Andrew J K Phillips and Martin K Rutter and Richa Saxena and Sean W Cain and Jacqueline M Lane},
doi = {10.1093/sleep/zsac287},
issn = {1550-9109},
year  = {2023},
date = {2023-03-01},
journal = {Sleep},
volume = {46},
number = {3},
abstract = {STUDY OBJECTIVES: Light is the primary stimulus for synchronizing the circadian clock in humans. There are very large interindividual differences in the sensitivity of the circadian clock to light. Little is currently known about the genetic basis for these interindividual differences.nnMETHODS: We performed a genome-wide gene-by-environment interaction study (GWIS) in 280 897 individuals from the UK Biobank cohort to identify genetic variants that moderate the effect of daytime light exposure on chronotype (individual time of day preference), acting as "light sensitivity" variants for the impact of daylight on the circadian system.nnRESULTS: We identified a genome-wide significant SNP mapped to the ARL14EP gene (rs3847634; p < 5 × 10-8), where additional minor alleles were found to enhance the morningness effect of daytime light exposure (βGxE = -.03, SE = 0.005) and were associated with increased gene ARL14EP expression in brain and retinal tissues. Gene-property analysis showed light sensitivity loci were enriched for genes in the G protein-coupled glutamate receptor signaling pathway and genes expressed in Per2+ hypothalamic neurons. Linkage disequilibrium score regression identified Bonferroni significant genetic correlations of greater light sensitivity GWIS with later chronotype and shorter sleep duration. Greater light sensitivity was nominally genetically correlated with insomnia symptoms and risk for post-traumatic stress disorder (PTSD).nnCONCLUSIONS: This study is the first to assess light as an important exposure in the genomics of chronotype and is a critical first step in uncovering the genetic architecture of human circadian light sensitivity and its links to sleep and mental health.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36928188,
title = {Multimodal CRISPR perturbations of GWAS loci associated with coronary artery disease in vascular endothelial cells},
author = {Florian Wünnemann and Thierry Fotsing Tadjo and Mélissa Beaudoin and Simon Lalonde and Ken Sin Lo and Benjamin P Kleinstiver and Guillaume Lettre},
doi = {10.1371/journal.pgen.1010680},
issn = {1553-7404},
year  = {2023},
date = {2023-03-01},
journal = {PLoS Genet},
volume = {19},
number = {3},
pages = {e1010680},
abstract = {Genome-wide association studies have identified >250 genetic variants associated with coronary artery disease (CAD), but the causal variants, genes and molecular mechanisms remain unknown at most loci. We performed pooled CRISPR screens to test the impact of sequences at or near CAD-associated genetic variants on vascular endothelial cell functions. Using CRISPR knockout, inhibition and activation, we targeted 1998 variants at 83 CAD loci to assess their effect on three adhesion proteins (E-selectin, ICAM1, VCAM1) and three key endothelial functions (nitric oxide and reactive oxygen species production, calcium signalling). At a false discovery rate ≤10%, we identified significant CRISPR perturbations near 42 variants located within 26 CAD loci. We used base editing to validate a putative causal variant in the promoter of the FES gene. Although a few of the loci include genes previously characterized in endothelial cells (e.g. AIDA, ARHGEF26, ADAMTS7), most are implicated in endothelial dysfunction for the first time. Detailed characterization of one of these new loci implicated the RNA helicase DHX38 in vascular endothelial cell senescence. While promising, our results also highlighted several limitations in using CRISPR perturbations to functionally dissect GWAS loci, including an unknown false negative rate and potential off-target effects.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36346311,
title = {Quantitative Brain Morphometry of Portable Low-Field-Strength MRI Using Super-Resolution Machine Learning},
author = {Juan Eugenio Iglesias and Riana Schleicher and Sonia Laguna and Benjamin Billot and Pamela Schaefer and Brenna McKaig and Joshua N Goldstein and Kevin N Sheth and Matthew S Rosen and W Taylor Kimberly},
doi = {10.1148/radiol.220522},
issn = {1527-1315},
year  = {2023},
date = {2023-03-01},
journal = {Radiology},
volume = {306},
number = {3},
pages = {e220522},
abstract = {Background Portable, low-field-strength (0.064-T) MRI has the potential to transform neuroimaging but is limited by low spatial resolution and low signal-to-noise ratio. Purpose To implement a machine learning super-resolution algorithm that synthesizes higher spatial resolution images (1-mm isotropic) from lower resolution T1-weighted and T2-weighted portable brain MRI scans, making them amenable to automated quantitative morphometry. Materials and Methods An external high-field-strength MRI data set (1-mm isotropic scans from the Open Access Series of Imaging Studies data set) and segmentations for 39 regions of interest (ROIs) in the brain were used to train a super-resolution convolutional neural network (CNN). Secondary analysis of an internal test set of 24 paired low- and high-field-strength clinical MRI scans in participants with neurologic symptoms was performed. These were part of a prospective observational study (August 2020 to December 2021) at Massachusetts General Hospital (exclusion criteria: inability to lay flat, body habitus preventing low-field-strength MRI, presence of MRI contraindications). Three well-established automated segmentation tools were applied to three sets of scans: high-field-strength (1.5-3 T, reference standard), low-field-strength (0.064 T), and synthetic high-field-strength images generated from the low-field-strength data with the CNN. Statistical significance of correlations was assessed with Student  tests. Correlation coefficients were compared with Steiger  tests. Results Eleven participants (mean age, 50 years ± 14; seven men) had full cerebrum coverage in the images without motion artifacts or large stroke lesion with distortion from mass effect. Direct segmentation of low-field-strength MRI yielded nonsignificant correlations with volumetric measurements from high field strength for most ROIs ( > .05). Correlations largely improved when segmenting the synthetic images:  values were less than .05 for all ROIs (eg, for the hippocampus [ = 0.85;  < .001], thalamus [ = 0.84;  = .001], and whole cerebrum [ = 0.92;  < .001]). Deviations from the model ( score maps) visually correlated with pathologic abnormalities. Conclusion This work demonstrated proof-of-principle augmentation of portable MRI with a machine learning super-resolution algorithm, which yielded highly correlated brain morphometric measurements to real higher resolution images. © RSNA, 2022  See also the editorial by Ertl-Wagner amd Wagner in this issue. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37034709,
title = {Untargeted metabolomics profiling in pediatric patients and adult populations indicates a connection between lipid imbalance and epilepsy},
author = {Kaisa Teele Oja and Mihkel Ilisson and Karit Reinson and Kai Muru and Tiia Reimand and Hedi Peterson and Dmytro Fishman and Tõnu Esko and Toomas Haller and Jaanika Kronberg and Monica H Wojcik and Adam Kennedy and Gregory Michelotti and Anne O'Donnell-Luria and Eve Õiglane-Šlik and Sander Pajusalu and Katrin Õunap},
doi = {10.1101/2023.03.29.23287640},
year  = {2023},
date = {2023-03-01},
journal = {medRxiv},
abstract = {INTRODUCTION: Epilepsy is a common central nervous system disorder characterized by abnormal brain electrical activity. We aimed to compare the metabolic profiles of plasma from patients with epilepsy across different etiologies, seizure frequency, seizure type, and patient age to try to identify common disrupted pathways.nnMATERIAL AND METHODS: We used data from three separate cohorts. The first cohort (PED-C) consisted of 31 pediatric patients with suspicion of a genetic disorder with unclear etiology; the second cohort (AD-C) consisted of 250 adults from the Estonian Biobank (EstBB), and the third cohort consisted of 583 adults ≥ 69 years of age from the EstBB (ELD-C). We compared untargeted metabolomics and lipidomics data between individuals with and without epilepsy in each cohort.nnRESULTS: In the PED-C, significant alterations (p-value <0.05) were detected in sixteen different glycerophosphatidylcholines (GPC), dimethylglycine and eicosanedioate (C20-DC). In the AD-C, nine significantly altered metabolites were found, mainly triacylglycerides (TAG), which are also precursors in the GPC synthesis pathway. In the ELD-C, significant changes in twenty metabolites including multiple TAGs were observed in the metabolic profile of participants with previously diagnosed epilepsy. Pathway analysis revealed that among the metabolites that differ significantly between epilepsy-positive and epilepsy-negative patients in the PED-C, the lipid superpathway (p = 3.2*10-4) and phosphatidylcholine (p = 9.3*10-8) and lysophospholipid (p = 5.9*10-3) subpathways are statistically overrepresented. Analogously, in the AD-C, the triacylglyceride subclass turned out to be statistically overrepresented (p = 8.5*10-5) with the lipid superpathway (p = 1.4*10-2). The presented p-values are FDR-corrected.nnCONCLUSION: Our results suggest that cell membrane fluidity may have a significant role in the mechanism of epilepsy, and changes in lipid balance may indicate epilepsy. However, further studies are needed to evaluate whether untargeted metabolomics analysis could prove helpful in diagnosing epilepsy earlier.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36993255,
title = {Small Molecule Regulators of microRNAs Identified by High-Throughput Screen Coupled with High-Throughput Sequencing},
author = {Anna Krichevsky and Lien Nguyen and Zhiyun Wei and M Silva and Sergio Barberán-Soler and Rosalia Rabinovsky and Christina Muratore and Jonathan Stricker and Colin Hortman and Tracy Young-Pearse and Stephen Haggarty},
doi = {10.21203/rs.3.rs-2617979/v1},
year  = {2023},
date = {2023-03-01},
journal = {Res Sq},
abstract = {MicroRNAs (miRNAs) regulate fundamental biological processes by silencing mRNA targets and are dysregulated in many diseases. Therefore, miRNA replacement or inhibition can be harnessed as potential therapeutics. However, existing strategies for miRNA modulation using oligonucleotides and gene therapies are challenging, especially for neurological diseases, and none have yet gained clinical approval. We explore a different approach by screening a biodiverse library of small molecule compounds for their ability to modulate hundreds of miRNAs in human induced pluripotent stem cell-derived neurons. We demonstrate the utility of the screen by identifying cardiac glycosides as potent inducers of miR-132, a key miRNA downregulated in Alzheimer's disease and other tauopathies. Coordinately, cardiac glycosides downregulate known miR-132 targets, including Tau, and protect rodent and human neurons against various toxic insults. More generally, our dataset of 1370 drug-like compounds and their effects on the miRNome provide a valuable resource for further miRNA-based drug discovery.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36440953,
title = {The relevance of rich club regions for functional outcome post-stroke is enhanced in women},
author = {Anna K Bonkhoff and Markus D Schirmer and Martin Bretzner and Sungmin Hong and Robert W Regenhardt and Kathleen L Donahue and Marco J Nardin and Adrian V Dalca and Anne-Katrin Giese and Mark R Etherton and Brandon L Hancock and Steven J T Mocking and Elissa C McIntosh and John Attia and John W Cole and Amanda Donatti and Christoph J Griessenauer and Laura Heitsch and Lukas Holmegaard and Katarina Jood and Jordi Jimenez-Conde and Steven J Kittner and Robin Lemmens and Christopher R Levi and Caitrin W McDonough and James F Meschia and Chia-Ling Phuah and Stefan Ropele and Jonathan Rosand and Jaume Roquer and Tatjana Rundek and Ralph L Sacco and Reinhold Schmidt and Pankaj Sharma and Agnieszka Slowik and Alessandro Sousa and Tara M Stanne and Daniel Strbian and Turgut Tatlisumak and Vincent Thijs and Achala Vagal and Johan Wasselius and Daniel Woo and Ramin Zand and Patrick F McArdle and Bradford B Worrall and Christina Jern and Arne G Lindgren and Jane Maguire and Ona Wu and Natalia S Rost and },
doi = {10.1002/hbm.26159},
issn = {1097-0193},
year  = {2023},
date = {2023-03-01},
journal = {Hum Brain Mapp},
volume = {44},
number = {4},
pages = {1579--1592},
abstract = {This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36876906,
title = {Identification of a weight loss-associated causal eQTL in  and the effects of  deficiency on human adipocyte function},
author = {Mi Huang and Daniel Coral and Hamidreza Ardalani and Peter Spegel and Alham Saadat and Melina Claussnitzer and Hindrik Mulder and Paul W Franks and Sebastian Kalamajski},
doi = {10.7554/eLife.84168},
issn = {2050-084X},
year  = {2023},
date = {2023-03-01},
journal = {Elife},
volume = {12},
abstract = {Genetic variation at the  (Mitochondrial Translational Initiation Factor 3) locus has been robustly associated with obesity in humans, but the functional basis behind this association is not known. Here, we applied luciferase reporter assay to map potential functional variants in the haplotype block tagged by rs1885988 and used CRISPR-Cas9 to edit the potential functional variants to confirm the regulatory effects on  expression. We further conducted functional studies on MTIF3-deficient differentiated human white adipocyte cell line (hWAs-iCas9), generated through inducible expression of CRISPR-Cas9 combined with delivery of synthetic -targeting guide RNA. We demonstrate that rs67785913-centered DNA fragment (in LD with rs1885988,  > 0.8) enhances transcription in a luciferase reporter assay, and CRISPR-Cas9-edited rs67785913 CTCT cells show significantly higher  expression than rs67785913 CT cells. Perturbed  expression led to reduced mitochondrial respiration and endogenous fatty acid oxidation, as well as altered expression of mitochondrial DNA-encoded genes and proteins, and disturbed mitochondrial OXPHOS complex assembly. Furthermore, after glucose restriction, the  knockout cells retained more triglycerides than control cells. This study demonstrates an adipocyte function-specific role of , which originates in the maintenance of mitochondrial function, providing potential explanations for why  genetic variation at rs67785913 is associated with body corpulence and response to weight loss interventions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36797366,
title = {Genetics of sexually dimorphic adipose distribution in humans},
author = {Grace T Hansen and Débora R Sobreira and Zachary T Weber and Alexis G Thornburg and Ivy Aneas and Li Zhang and Noboru J Sakabe and Amelia C Joslin and Gabriela A Haddad and Sophie M Strobel and Samantha Laber and Farhath Sultana and Faezeh Sahebdel and Kohinoor Khan and Yang I Li and Melina Claussnitzer and Liang Ye and Ricardo A Battaglino and Marcelo A Nóbrega},
doi = {10.1038/s41588-023-01306-0},
issn = {1546-1718},
year  = {2023},
date = {2023-03-01},
journal = {Nat Genet},
volume = {55},
number = {3},
pages = {461--470},
abstract = {Obesity-associated morbidity is exacerbated by abdominal obesity, which can be measured as the waist-to-hip ratio adjusted for the body mass index (WHRadjBMI). Here we identify genes associated with obesity and WHRadjBMI and characterize allele-sensitive enhancers that are predicted to regulate WHRadjBMI genes in women. We found that several waist-to-hip ratio-associated variants map within primate-specific Alu retrotransposons harboring a DNA motif associated with adipocyte differentiation. This suggests that a genetic component of adipose distribution in humans may involve co-option of retrotransposons as adipose enhancers. We evaluated the role of the strongest female WHRadjBMI-associated gene, SNX10, in adipose biology. We determined that it is required for human adipocyte differentiation and function and participates in diet-induced adipose expansion in female mice, but not males. Our data identify genes and regulatory mechanisms that underlie female-specific adipose distribution and mediate metabolic dysfunction in women.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36961462,
title = {Association Between Ghrelin and Body Weight Trajectory in Individuals With Anorexia Nervosa},
author = {Youngjung R Kim and Meghan S Lauze and Meghan Slattery and Roy H Perlis and Laura M Holsen and Lauren Breithaupt and Casey M Stern and Maurizio Fava and Jennifer J Thomas and Elizabeth A Lawson and Madhusmita Misra and Kamryn T Eddy},
doi = {10.1001/jamanetworkopen.2023.4625},
issn = {2574-3805},
year  = {2023},
date = {2023-03-01},
journal = {JAMA Netw Open},
volume = {6},
number = {3},
pages = {e234625},
abstract = {IMPORTANCE: Individuals with anorexia nervosa maintain extremely low body weights despite elevations in the circulating orexigenic hormone ghrelin. Whether circulating levels of endogenous ghrelin are associated with weight gain in anorexia nervosa is unknown.nnOBJECTIVE: To examine the association between baseline ghrelin and future weight change in individuals with anorexia nervosa.nnDESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted between April 1, 2014, and March 31, 2020, in the US. Girls and women aged 10 to 22 years were recruited from the greater Boston area from community and area treatment centers, enrolled, and followed up for 18 months. Statistical analyses were performed between January and August 2022.nnEXPOSURES: Presence or absence of anorexia nervosa and elevations in endogenous ghrelin.nnMAIN OUTCOMES AND MEASURES: Changes in age- and sex-standardized body mass index percentiles from baseline to 9- and 18-month follow-up were the main outcomes of interest.nnRESULTS: A total of 68 girls and young women (11 [16%] Asian, 4 [6%] Hispanic or Latina, 51 [75%] White [non-Hispanic or Latina], and 2 [3%] other race or ethnicity), including 35 with anorexia nervosa and 33 healthy controls of similar Tanner stage, were included in this study. Anorexia nervosa and healthy control groups were not statistically different by race and ethnicity, Tanner stage, number completing follow-up visits, and the duration between baseline and follow-up visits. At baseline, individuals with anorexia nervosa were slightly older (median [IQR], 20.1 [18.5-21.0] vs 18.7 [14.7-19.4] years; P = .005), had lower body mass index percentiles (median [IQR], 2.4 [0.3-4.7] vs 52.9 [40.4-68.3]; P < .001), and had elevated circulating ghrelin area under the curve composite index (median [IQR], 1389.4 [1082.5-1646.4] vs 958.5 [743.0-1234.5] pg/mL; P = .003) compared with healthy individuals. In linear mixed-effects regression analyses, baseline ghrelin was associated with prospective weight gain after adjusting for diagnosis, age, race, and duration of follow-up (odds ratio, 2.35; 95% CI, 1.43-3.73; P = .004).nnCONCLUSIONS AND RELEVANCE: In this cohort study, endogenous ghrelin was associated with longitudinal weight gain in individuals with anorexia nervosa. Further studies are warranted to confirm this result and examine its potential clinical utility in treatment development.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37034588,
title = {Translatome analysis of Tuberous Sclerosis Complex-1 patient-derived neural progenitor cells reveal rapamycin-dependent and independent alterations},
author = {Inci Aksoylu and Pauline Martin and Francis Robert and Krzysztof Szkop and Nicholas Redmond and Shan Chen and Roberta Beauchamp and Irene Nobeli and Jerry Pelletier and Ola Larsson and Vijaya Ramesh},
doi = {10.21203/rs.3.rs-2702044/v1},
year  = {2023},
date = {2023-03-01},
journal = {Res Sq},
abstract = {Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in  or  genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD). The hamartin-tuberin (TSC1-TSC2) protein complex inactivates mechanistic target of rapamycin complex 1 (mTORC1) signaling, leading to increased protein synthesis via inactivation of translational repressor eIF4E-binding proteins (4E-BPs). In  -null neural progenitor cells (NPCs), we previously reported early ND phenotypic changes, including increased proliferation/altered neurite outgrowth, which were unaffected by mTORC1-inhibitor rapamycin. Here, using polysome-profiling to quantify translational efficiencies at a transcriptome-wide level, we observed numerous TSC1-dependent alterations in NPCs, largely recapitulated in post-mortem brains from ASD donors. Although rapamycin partially reversed TSC1-associated alterations, most neural activity/synaptic- or ASD-related genes remained insensitive but were inhibited by third-generation bi-steric, mTORC1-selective inhibitor RMC-6272, which also reversed altered ND phenotypes. Together these data reveal potential implications for treatment of TAND.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36309041,
title = {Intracerebral haemorrhage expansion: definitions, predictors, and prevention},
author = {Andrea Morotti and Gregoire Boulouis and Dar Dowlatshahi and Qi Li and Michel Shamy and Rustam Al-Shahi Salman and Jonathan Rosand and Charlotte Cordonnier and Joshua N Goldstein and Andreas Charidimou},
doi = {10.1016/S1474-4422(22)00338-6},
issn = {1474-4465},
year  = {2023},
date = {2023-02-01},
journal = {Lancet Neurol},
volume = {22},
number = {2},
pages = {159--171},
abstract = {Haematoma expansion affects a fifth of patients within 24 h of the onset of acute intracerebral haemorrhage and is associated with death and disability, which makes it an appealing therapeutic target. The time in which active intervention can be done is short as expansion occurs mostly within the first 3 h after onset. Baseline haemorrhage volume, antithrombotic treatment, and CT angiography spot signs are each associated with increased risk of haematoma expansion. Non-contrast CT features are promising predictors of haematoma expansion, but their potential contribution to current models is under investigation. Blood pressure lowering and haemostatic treatment minimise haematoma expansion but have not led to improved functional outcomes in randomised clinical trials. Ultra-early enrolment and selection of participants on the basis of non-contrast CT imaging markers could focus future clinical trials to show clinical benefit in people at high risk of expansion or investigate heterogeneity of treatment effects in clinical trials with broad inclusion criteria.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36865150,
title = {Shared and distinct ultra-rare genetic risk for diverse epilepsies: A whole-exome sequencing study of 54,423 individuals across multiple genetic ancestries},
author = { and Siwei Chen and Benjamin M Neale and Samuel F Berkovic},
doi = {10.1101/2023.02.22.23286310},
year  = {2023},
date = {2023-02-01},
journal = {medRxiv},
abstract = {Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date to investigate rare variants that confer risk for a spectrum of epilepsy syndromes. With an unprecedented sample size of >54,000 human exomes, composed of 20,979 deep-phenotyped patients with epilepsy and 33,444 controls, we replicate previous gene findings at exome-wide significance; using a hypothesis-free approach, we identify potential novel associations. Most discoveries are specific to a particular subtype of epilepsy, highlighting distinct genetic contributions to different epilepsies. Combining evidence from rare single nucleotide/short indel-, copy number-, and common variants, we find convergence of different genetic risk factors at the level of individual genes. Further comparing to other exome-sequencing studies, we implicate shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our study also demonstrates the value of collaborative sequencing and deep-phenotyping efforts, which will continue to unravel the complex genetic architecture underlying the heterogeneity of epilepsy.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36689586,
title = {Sex Differences in Onset and Progression of Cerebral Amyloid Angiopathy},
author = {Emma A Koemans and Juan Pablo Castello and Ingeborg Rasing and Jessica R Abramson and Sabine Voigt and Valentina Perosa and Thijs W van Harten and Erik W van Zwet and Gisela M Terwindt and M Edip Gurol and Jonathan Rosand and Steven M Greenberg and Marianne A A van Walderveen and Alessandro Biffi and Anand Viswanathan and Marieke J H Wermer},
doi = {10.1161/STROKEAHA.122.040823},
issn = {1524-4628},
year  = {2023},
date = {2023-02-01},
journal = {Stroke},
volume = {54},
number = {2},
pages = {306--314},
abstract = {BACKGROUND: Cerebral Amyloid Angiopathy (CAA) disease course is highly variable even in hereditary forms. Sex may be a possible modifying factor. We investigated biological sex differences in clinical disease course and magnetic resonance imaging-markers in sporadic (sCAA) and Dutch-type hereditary CAA (D-CAA).nnMETHODS: Patients with D-CAA and sCAA were included from hospital and research databases of the Leiden University Medical Center (2012-2020) and Massachusetts General Hospital (1994-2012). Key outcomes were: sex differences in symptomatic intracerebral hemorrhage (sICH) onset, recurrence and survival (analyzed using Kaplan Meier survival and regression analyses), and sex differences in magnetic resonance imaging-markers in D-CAA (explored using scatterplots), and in sCAA (investigated using regression analysis).nnRESULTS: We included 136 patients with D-CAA (mean age 57 years, 56% women, 64% with previous sICH) and 370 patients with sCAA (mean age 76 years, 51% women, all with previous sICH). Men and women with D-CAA did not differ for sICH onset (median age 54 in men and 56 in women [=0.13]). Men with D-CAA had a slightly higher number of sICH compared with women (median 2 versus 1; adjusted RR, 1.5 [95% CI, 1.1-1.9]) and a shorter interval between the first and second sICH (median 1.8 years for men and 3.1 years for women, =0.02). Men with sCAA had their first sICH at an earlier age (median 75 versus 78 years, respectively, =0.003) and more lobar microbleeds (median 1 versus 0, =0.022) compared with women with sCAA. No substantial differences were found in the other magnetic resonance imaging markers. Survival after first sICH was comparable between sexes for D-CAA (=0.12) and sCAA (=0.23).nnCONCLUSIONS: Men with CAA seem to have an earlier onset (sCAA) and more hemorrhagic disease course (sCAA and D-CAA) compared with women. Future studies are necessary to confirm these findings and determine the underlying role of sex-related factors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36865221,
title = {FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity},
author = {Nicolas Wieder and Juliana Coraor Fried and Choah Kim and Eriene-Heidi Sidhom and Matthew R Brown and Jamie L Marshall and Carlos Arevalo and Moran Dvela-Levitt and Maria Kost-Alimova and Jonas Sieber and Katlyn R Gabriel and Julian Pacheco and Clary Clish and Hamdah Shafqat Abbasi and Shantanu Singh and Justine Rutter and Martine Therrien and Haejin Yoon and Zon Weng Lai and Aaron Baublis and Renuka Subramanian and Ranjan Devkota and Jonnell Small and Vedagopuram Sreekanth and Myeonghoon Han and Donghyun Lim and Anne E Carpenter and Jason Flannick and Hilary Finucane and Marcia C Haigis and Melina Claussnitzer and Eric Sheu and Beth Stevens and Bridget K Wagner and Amit Choudhary and Jillian L Shaw and Juan Lorenzo Pablo and Anna Greka},
doi = {10.1101/2023.02.19.529127},
year  = {2023},
date = {2023-02-01},
journal = {bioRxiv},
abstract = {Cellular exposure to free fatty acids (FFA) is implicated in the pathogenesis of obesity-associated diseases. However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and there are no scalable approaches to comprehensively assess the biological processes induced by exposure to diverse FFAs circulating in human plasma. Furthermore, assessing how these FFA- mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (Fatty Acid Library for Comprehensive ONtologies) as an unbiased, scalable and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids (MUFAs) with a distinct lipidomic profile associated with decreased membrane fluidity. Furthermore, we developed a new approach to prioritize genes that reflect the combined effects of exposure to harmful FFAs and genetic risk for type 2 diabetes (T2D). Importantly, we found that c-MAF inducing protein (CMIP) protects cells from exposure to FFAs by modulating Akt signaling and we validated the role of CMIP in human pancreatic beta cells. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.nnHIGHLIGHTS: FALCON (Fatty Acid Library for Comprehensive ONtologies) enables multimodal profiling of 61 free fatty acids (FFAs) to reveal 5 FFA clusters with distinct biological effectsFALCON is applicable to many and diverse cell typesA subset of monounsaturated FAs (MUFAs) equally or more toxic than canonical lipotoxic saturated FAs (SFAs) leads to decreased membrane fluidityNew approach prioritizes genes that represent the combined effects of environmental (FFA) exposure and genetic risk for diseaseC-Maf inducing protein (CMIP) is identified as a suppressor of FFA-induced lipotoxicity via Akt-mediated signaling.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36547967,
title = {Association of Metformin With the Development of Age-Related Macular Degeneration},
author = {Amitha Domalpally and Samuel A Whittier and Qing Pan and Dana M Dabelea and Christine H Darwin and William C Knowler and Christine G Lee and Jose A Luchsinger and Neil H White and Emily Y Chew and },
doi = {10.1001/jamaophthalmol.2022.5567},
issn = {2168-6173},
year  = {2023},
date = {2023-02-01},
journal = {JAMA Ophthalmol},
volume = {141},
number = {2},
pages = {140--147},
abstract = {IMPORTANCE: Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD.nnOBJECTIVE: To investigate the association between metformin use and age-related macular degeneration (AMD).nnDESIGN, SETTING, AND PARTICIPANTS: The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022.nnINTERVENTIONS: Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo.nnMAIN OUTCOMES AND MEASURES: Prevalence of AMD in the treatment arms.nnRESULTS: Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02).nnCONCLUSIONS AND RELEVANCE: These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36702997,
title = {Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains},
author = {Ditte Demontis and G Bragi Walters and Georgios Athanasiadis and Raymond Walters and Karen Therrien and Trine Tollerup Nielsen and Leila Farajzadeh and Georgios Voloudakis and Jaroslav Bendl and Biau Zeng and Wen Zhang and Jakob Grove and Thomas D Als and Jinjie Duan and F Kyle Satterstrom and Jonas Bybjerg-Grauholm and Marie Bækved-Hansen and Olafur O Gudmundsson and Sigurdur H Magnusson and Gisli Baldursson and Katrin Davidsdottir and Gyda S Haraldsdottir and Esben Agerbo and Gabriel E Hoffman and Søren Dalsgaard and Joanna Martin and Marta Ribasés and Dorret I Boomsma and Maria Soler Artigas and Nina Roth Mota and Daniel Howrigan and Sarah E Medland and Tetyana Zayats and Veera M Rajagopal and  and  and Merete Nordentoft and Ole Mors and David M Hougaard and Preben Bo Mortensen and Mark J Daly and Stephen V Faraone and Hreinn Stefansson and Panos Roussos and Barbara Franke and Thomas Werge and Benjamin M Neale and Kari Stefansson and Anders D Børglum},
doi = {10.1038/s41588-022-01285-8},
issn = {1546-1718},
year  = {2023},
date = {2023-02-01},
journal = {Nat Genet},
volume = {55},
number = {2},
pages = {198--208},
abstract = {Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36793015,
title = {Causal relationships between migraine and microstructural white matter: a Mendelian randomization study},
author = {Lei Zhao and Wenhui Zhao and  and Jin Cao and Yiheng Tu},
doi = {10.1186/s10194-023-01550-z},
issn = {1129-2377},
year  = {2023},
date = {2023-02-01},
journal = {J Headache Pain},
volume = {24},
number = {1},
pages = {10},
abstract = {BACKGROUND: Migraine is a disabling neurological disorder with the pathophysiology yet to be understood. The microstructural alteration in brain white matter (WM) has been suggested to be related to migraine in recent studies, but these evidence are observational essentially and cannot infer a causal relationship. The present study aims to reveal the causal relationship between migraine and microstructural WM using genetic data and Mendelian randomization (MR).nnMETHODS: We collected the Genome-wide association study (GWAS) summary statistics of migraine (48,975 cases / 550,381 controls) and 360 WM imaging-derived phenotypes (IDPs) (31,356 samples) that were used to measure microstructural WM. Based on instrumental variables (IVs) selected from the GWAS summary statistics, we conducted bidirectional two-sample MR analyses to infer bidirectional causal associations between migraine and microstructural WM. In forward MR analysis, we inferred the causal effect of microstructural WM on migraine by reporting the odds ratio (OR) that quantified the risk change of migraine for per 1 standard deviation (SD) increase of IDPs. In reverse MR analysis, we inferred the causal effect of migraine on microstructural WM by reporting the β value that represented SDs of changes in IDPs were caused by migraine.nnRESULTS: Three WM IDPs showed significant causal associations (p < 3.29 × 10, Bonferroni correction) with migraine and were proved to be reliable via sensitivity analysis. The mode of anisotropy (MO) of left inferior fronto-occipital fasciculus (OR = 1.76, p = 6.46 × 10) and orientation dispersion index (OD) of right posterior thalamic radiation (OR = 0.78, p = 1.86 × 10) exerted significant causal effects on migraine. Migraine exerted a significant causal effect on the OD of left superior cerebellar peduncle (β = - 0.09, p = 2.78 × 10).nnCONCLUSIONS: Our findings provided genetic evidence for the causal relationships between migraine and microstructural WM, bringing new insights into brain structure for the development and experience of migraine.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36726022,
title = {Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata},
author = {Eeva Sliz and Jaakko S Tyrmi and Nilufer Rahmioglu and Krina T Zondervan and Christian M Becker and  and Outi Uimari and Johannes Kettunen},
doi = {10.1038/s41467-023-35974-7},
issn = {2041-1723},
year  = {2023},
date = {2023-02-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {542},
abstract = {Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1 A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36265505,
title = {Raising the bar for measuring childhood adversity},
author = {Kristen Choi and Alexy Arauz Boudreau and Erin C Dunn},
doi = {10.1016/S2352-4642(22)00301-7},
issn = {2352-4650},
year  = {2023},
date = {2023-02-01},
journal = {Lancet Child Adolesc Health},
volume = {7},
number = {2},
pages = {81--83},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36443016,
title = {Radiomics-Derived Brain Age Predicts Functional Outcome After Acute Ischemic Stroke},
author = {Martin Bretzner and Anna K Bonkhoff and Markus D Schirmer and Sungmin Hong and Adrian Dalca and Kathleen Donahue and Anne-Katrin Giese and Mark R Etherton and Pamela M Rist and Marco Nardin and Robert W Regenhardt and Xavier Leclerc and Renaud Lopes and Morgan Gautherot and Clinton Wang and Oscar R Benavente and John W Cole and Amanda Donatti and Christoph Griessenauer and Laura Heitsch and Lukas Holmegaard and Katarina Jood and Jordi Jimenez-Conde and Steven J Kittner and Robin Lemmens and Christopher R Levi and Patrick F McArdle and Caitrin W McDonough and James F Meschia and Chia-Ling Phuah and Arndt Rolfs and Stefan Ropele and Jonathan Rosand and Jaume Roquer and Tatjana Rundek and Ralph L Sacco and Reinhold Schmidt and Pankaj Sharma and Agnieszka Slowik and Alessandro Sousa and Tara M Stanne and Daniel Strbian and Turgut Tatlisumak and Vincent Thijs and Achala Vagal and Johan Wasselius and Daniel Woo and Ona Wu and Ramin Zand and Bradford B Worrall and Jane Maguire and Arne G Lindgren and Christina Jern and Polina Golland and Grégory Kuchcinski and Natalia S Rost and },
doi = {10.1212/WNL.0000000000201596},
issn = {1526-632X},
year  = {2023},
date = {2023-02-01},
journal = {Neurology},
volume = {100},
number = {8},
pages = {e822--e833},
abstract = {BACKGROUND AND OBJECTIVES: While chronological age is one of the most influential determinants of poststroke outcomes, little is known of the impact of neuroimaging-derived biological "brain age." We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of patients with stroke will be associated with cardiovascular risk factors and worse functional outcomes.nnMETHODS: We extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison with chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs and a logistic regression model of favorable functional outcomes taking RBA as input.nnRESULTS: We reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age = 62.8 years, 42.0% female patients). T2-FLAIR radiomics predicted chronological ages (mean absolute error = 6.9 years,  = 0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted odds ratios: 0.58, 0.76, 0.48, 0.55; all -values < 0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes.nnDISCUSSION: T2-FLAIR radiomics can be used to predict brain age and derive RBA. Older-appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36765070,
title = {Bi-allelic ATG4D variants are associated with a neurodevelopmental disorder characterized by speech and motor impairment},
author = {Marie Morimoto and Vikas Bhambhani and Nour Gazzaz and Mariska Davids and Paalini Sathiyaseelan and Ellen F Macnamara and Jennifer Lange and Anna Lehman and Patricia M Zerfas and Jennifer L Murphy and Maria T Acosta and Camille Wang and Emily Alderman and  and Sara Reichert and Audrey Thurm and David R Adams and Wendy J Introne and Sharon M Gorski and Cornelius F Boerkoel and William A Gahl and Cynthia J Tifft and May Christine V Malicdan},
doi = {10.1038/s41525-022-00343-8},
issn = {2056-7944},
year  = {2023},
date = {2023-02-01},
journal = {NPJ Genom Med},
volume = {8},
number = {1},
pages = {4},
abstract = {Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or "primed" by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36253440,
title = {Genome-wide association study meta-analysis of suicide death and suicidal behavior},
author = {Qingqin S Li and Andrey A Shabalin and Emily DiBlasi and Srihari Gopal and Carla M Canuso and  and Aarno Palotie and Wayne C Drevets and Anna R Docherty and Hilary Coon},
doi = {10.1038/s41380-022-01828-9},
issn = {1476-5578},
year  = {2023},
date = {2023-02-01},
journal = {Mol Psychiatry},
volume = {28},
number = {2},
pages = {891--900},
abstract = {Suicide is a worldwide health crisis. We aimed to identify genetic risk variants associated with suicide death and suicidal behavior. Meta-analysis for suicide death was performed using 3765 cases from Utah and matching 6572 controls of European ancestry. Meta-analysis for suicidal behavior using data across five cohorts (n = 8315 cases and 256,478 psychiatric or populational controls of European ancestry) was also performed. One locus in neuroligin 1 (NLGN1) passing the genome-wide significance threshold for suicide death was identified (top SNP rs73182688, with p = 5.48 × 10 before and p = 4.55 × 10 after mtCOJO analysis conditioning on MDD to remove genetic effects on suicide mediated by MDD). Conditioning on suicidal attempts did not significantly change the association strength (p = 6.02 × 10), suggesting suicide death specificity. NLGN1 encodes a member of a family of neuronal cell surface proteins. Members of this family act as splice site-specific ligands for beta-neurexins and may be involved in synaptogenesis. The NRXN-NLGN pathway was previously implicated in suicide, autism, and schizophrenia. We additionally identified ROBO2 and ZNF28 associations with suicidal behavior in the meta-analysis across five cohorts in gene-based association analysis using MAGMA. Lastly, we replicated two loci including variants near SOX5 and LOC101928519 associated with suicidal attempts identified in the ISGC and MVP meta-analysis using the independent FinnGen samples. Suicide death and suicidal behavior showed positive genetic correlations with depression, schizophrenia, pain, and suicidal attempt, and negative genetic correlation with educational attainment. These correlations remained significant after conditioning on depression, suggesting pleiotropic effects among these traits. Bidirectional generalized summary-data-based Mendelian randomization analysis suggests that genetic risk for the suicidal attempt and suicide death are both bi-directionally causal for MDD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36693378,
title = {Loci for insulin processing and secretion provide insight into type 2 diabetes risk},
author = {K Alaine Broadaway and Xianyong Yin and Alice Williamson and Victoria A Parsons and Emma P Wilson and Anne H Moxley and Swarooparani Vadlamudi and Arushi Varshney and Anne U Jackson and Vasudha Ahuja and Stefan R Bornstein and Laura J Corbin and Graciela E Delgado and Om P Dwivedi and Lilian Fernandes Silva and Timothy M Frayling and Harald Grallert and Stefan Gustafsson and Liisa Hakaste and Ulf Hammar and Christian Herder and Sandra Herrmann and Kurt Højlund and David A Hughes and Marcus E Kleber and Cecilia M Lindgren and Ching-Ti Liu and Jian'an Luan and Anni Malmberg and Angela P Moissl and Andrew P Morris and Nikolaos Perakakis and Annette Peters and John R Petrie and Michael Roden and Peter E H Schwarz and Sapna Sharma and Angela Silveira and Rona J Strawbridge and Tiinamaija Tuomi and Andrew R Wood and Peitao Wu and Björn Zethelius and Damiano Baldassarre and Johan G Eriksson and Tove Fall and Jose C Florez and Andreas Fritsche and Bruna Gigante and Anders Hamsten and Eero Kajantie and Markku Laakso and Jari Lahti and Deborah A Lawlor and Lars Lind and Winfried März and James B Meigs and Johan Sundström and Nicholas J Timpson and Robert Wagner and Mark Walker and Nicholas J Wareham and Hugh Watkins and Inês Barroso and Stephen O'Rahilly and Niels Grarup and Stephen Cj Parker and Michael Boehnke and Claudia Langenberg and Eleanor Wheeler and Karen L Mohlke},
doi = {10.1016/j.ajhg.2023.01.002},
issn = {1537-6605},
year  = {2023},
date = {2023-02-01},
journal = {Am J Hum Genet},
volume = {110},
number = {2},
pages = {284--299},
abstract = {Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36823209,
title = {Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome},
author = {Pritesh Jain and Tyne Miller-Fleming and Apostolia Topaloudi and Dongmei Yu and Petros Drineas and Marianthi Georgitsi and Zhiyu Yang and Renata Rizzo and Kirsten R Müller-Vahl and Zeynep Tumer and Nanette Mol Debes and Andreas Hartmann and Christel Depienne and Yulia Worbe and Pablo Mir and Danielle C Cath and Dorret I Boomsma and Veit Roessner and Tomasz Wolanczyk and Piotr Janik and Natalia Szejko and Cezary Zekanowski and Csaba Barta and Zsofia Nemoda and Zsanett Tarnok and Joseph D Buxbaum and Dorothy Grice and Jeffrey Glennon and Hreinn Stefansson and Bastian Hengerer and Noa Benaroya-Milshtein and Francesco Cardona and Tammy Hedderly and Isobel Heyman and Chaim Huyser and Astrid Morer and Norbert Mueller and Alexander Munchau and Kerstin J Plessen and Cesare Porcelli and Susanne Walitza and Anette Schrag and Davide Martino and  and  and Andrea Dietrich and  and Carol A Mathews and Jeremiah M Scharf and Pieter J Hoekstra and Lea K Davis and Peristera Paschou},
doi = {10.1038/s41398-023-02341-5},
issn = {2158-3188},
year  = {2023},
date = {2023-02-01},
journal = {Transl Psychiatry},
volume = {13},
number = {1},
pages = {69},
abstract = {Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36681445,
title = {Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial},
author = {Wolfgang Köhler and Marc Engelen and Florian Eichler and Robin Lachmann and Ali Fatemi and Jacinda Sampson and Ettore Salsano and Josep Gamez and Maria Judit Molnar and Sílvia Pascual and Maria Rovira and Anna Vilà and Guillem Pina and Itziar Martín-Ugarte and Adriana Mantilla and Pilar Pizcueta and Laura Rodríguez-Pascau and Estefania Traver and Anna Vilalta and María Pascual and Marc Martinell and Uwe Meya and Fanny Mochel and },
doi = {10.1016/S1474-4422(22)00495-1},
issn = {1474-4465},
year  = {2023},
date = {2023-02-01},
journal = {Lancet Neurol},
volume = {22},
number = {2},
pages = {127--136},
abstract = {BACKGROUND: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.nnMETHODS: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.nnFINDINGS: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group.nnINTERPRETATION: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.nnFUNDING: Minoryx Therapeutics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36798188,
title = {Prediction of Preeclampsia from Clinical and Genetic Risk Factors in Early and Late Pregnancy Using Machine Learning and Polygenic Risk Scores},
author = {Vesela P Kovacheva and Braden W Eberhard and Raphael Y Cohen and Matthew Maher and Richa Saxena and Kathryn J Gray},
doi = {10.1101/2023.02.03.23285385},
year  = {2023},
date = {2023-02-01},
journal = {medRxiv},
abstract = {BACKGROUND: Preeclampsia, a pregnancy-specific condition associated with new-onset hypertension after 20 weeks gestation, is a leading cause of maternal and neonatal morbidity and mortality. Predictive tools to understand which individuals are most at risk are needed.nnMETHODS: We identified a cohort of N=1,125 pregnant individuals who delivered between 05/2015-05/2022 at Mass General Brigham hospitals with available electronic health record (EHR) data and linked genetic data. Using clinical EHR data and systolic blood pressure polygenic risk scores (SBP PRS) derived from a large genome-wide association study, we developed machine learning (xgboost) and linear regression models to predict preeclampsia risk.nnRESULTS: Pregnant individuals with an SBP PRS in the top quartile had higher blood pressures throughout pregnancy compared to patients within the lowest quartile SBP PRS. In the first trimester, the most predictive model was xgboost, with an area under the curve (AUC) of 0.73. Adding the SBP PRS to the models improved the performance only of the linear regression model from AUC 0.70 to 0.71; the predictive power of other models remained unchanged. In late pregnancy, with data obtained up to the delivery admission, the best performing model was xgboost using clinical variables, which achieved an AUC of 0.91.nnCONCLUSIONS: Integrating clinical and genetic factors into predictive models can inform personalized preeclampsia risk and achieve higher predictive power than the current practice. In the future, personalized tools can be implemented in clinical practice to identify high-risk patients for preventative therapies and timely intervention to improve adverse maternal and neonatal outcomes.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36738982,
title = {Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome},
author = {Fotis Tsetsos and Apostolia Topaloudi and Pritesh Jain and Zhiyu Yang and Dongmei Yu and Petros Kolovos and Zeynep Tumer and Renata Rizzo and Andreas Hartmann and Christel Depienne and Yulia Worbe and Kirsten R Müller-Vahl and Danielle C Cath and Dorret I Boomsma and Tomasz Wolanczyk and Cezary Zekanowski and Csaba Barta and Zsofia Nemoda and Zsanett Tarnok and Shanmukha S Padmanabhuni and Joseph D Buxbaum and Dorothy Grice and Jeffrey Glennon and Hreinn Stefansson and Bastian Hengerer and Evangelia Yannaki and John A Stamatoyannopoulos and Noa Benaroya-Milshtein and Francesco Cardona and Tammy Hedderly and Isobel Heyman and Chaim Huyser and Pablo Mir and Astrid Morer and Norbert Mueller and Alexander Munchau and Kerstin J Plessen and Cesare Porcelli and Veit Roessner and Susanne Walitza and Anette Schrag and Davide Martino and  and  and  and  and  and  and Jay A Tischfield and Gary A Heiman and A Jeremy Willsey and Andrea Dietrich and Lea K Davis and James J Crowley and Carol A Mathews and Jeremiah M Scharf and Marianthi Georgitsi and Pieter J Hoekstra and Peristera Paschou},
doi = {10.1016/j.biopsych.2023.01.023},
issn = {1873-2402},
year  = {2023},
date = {2023-02-01},
journal = {Biol Psychiatry},
abstract = {BACKGROUND: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year.nnMETHODS: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants.nnRESULTS: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume.nnCONCLUSIONS: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36335070,
title = {The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study},
author = {Frank R Wendt and Miguel Garcia-Argibay and Brenda Cabrera-Mendoza and Unnur A Valdimarsdóttir and Joel Gelernter and Murray B Stein and Michel G Nivard and Adam X Maihofer and  and Caroline M Nievergelt and Henrik Larsson and Manuel Mattheisen and Renato Polimanti and Sandra M Meier},
doi = {10.1016/j.biopsych.2022.08.012},
issn = {1873-2402},
year  = {2023},
date = {2023-02-01},
journal = {Biol Psychiatry},
volume = {93},
number = {4},
pages = {362--369},
abstract = {BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship.nnMETHODS: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons).nnRESULTS: ADHD and PTSD had consistent r (r range, 0.43-0.52; p <  .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186-0.552; p = 7.68 × 10). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98-3.53).nnCONCLUSIONS: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36755099,
title = {Polygenic architecture of rare coding variation across 394,783 exomes},
author = {Daniel J Weiner and Ajay Nadig and Karthik A Jagadeesh and Kushal K Dey and Benjamin M Neale and Elise B Robinson and Konrad J Karczewski and Luke J O'Connor},
doi = {10.1038/s41586-022-05684-z},
issn = {1476-4687},
year  = {2023},
date = {2023-02-01},
journal = {Nature},
volume = {614},
number = {7948},
pages = {492--499},
abstract = {Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes. However, rare-variant genetic architecture is not well characterized, and the relationship between common-variant and rare-variant architecture is unclear. Here we quantify the heritability explained by the gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 UK Biobank exomes. Rare coding variants (allele frequency < 1 × 10) explain 1.3% (s.e. = 0.03%) of phenotypic variance on average-much less than common variants-and most burden heritability is explained by ultrarare loss-of-function variants (allele frequency < 1 × 10). Common and rare variants implicate the same cell types, with similar enrichments, and they have pleiotropic effects on the same pairs of traits, with similar genetic correlations. They partially colocalize at individual genes and loci, but not to the same extent: burden heritability is strongly concentrated in significant genes, while common-variant heritability is more polygenic, and burden heritability is also more strongly concentrated in constrained genes. Finally, we find that burden heritability for schizophrenia and bipolar disorder is approximately 2%. Our results indicate that rare coding variants will implicate a tractable number of large-effect genes, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36778246,
title = {A  missense variant in  associated with developmental delay exhibits functional deficits in },
author = {Sharayu Jangam and Lauren C Briere and Kristy Jay and Jonathan C Andrews and Melissa A Walker and Lance H Rodan and Frances A High and  and Shinya Yamamoto and David A Sweetser and Michael Wangler},
doi = {10.1101/2023.01.31.23285113},
year  = {2023},
date = {2023-02-01},
journal = {medRxiv},
abstract = { (  , a Polycomb Repressive Complex-2 (PRC2) component, is involved in a myriad of cellular processes through modifying histone 3 lysine27 (H3K27) residues.  represses transcription of downstream target genes through H3K27 trimethylation (H3K27me3). Genetic mutations in histone modifiers have been associated with developmental disorders, while  has not yet been linked to any human disease. However, the paralog  is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a  variant in  , p.Ala678Gly, through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and was the best candidate variant found in the exome. Human  /  are homologous to fly  , an essential gene in flies, and the residue (A678 in humans, A691 in  ) is conserved. To further study this variant, we obtained  null alleles and generated transgenic flies expressing wild-type    and the variant    . The   variant led to hyper H3K27me3 while the   did not, suggesting this is as a gain-of-function allele. When expressed under the tubulin promotor  the variant rescued null-lethality similar to wild-type but the   flies exhibit bang sensitivity and shortened lifespan. In conclusion, here we present a novel  variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in  . Biochemically this allele leads to increased H3K27me3 suggesting gain-of-function, but when expressed in adult flies the   has some characteristics of partial loss-of-function which may suggest it is a more complex allele  .},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36610321,
title = {Long-term effects of l-serine supplementation upon a mouse model of diabetic neuropathy},
author = {Chuying Xia and Saranya Suriyanarayanan and Yi Gong and Vera Fridman and Martin Selig and Jia Li and Seward Rutkove and Thorsten Hornemann and Florian Eichler},
doi = {10.1016/j.jdiacomp.2022.108383},
issn = {1873-460X},
year  = {2023},
date = {2023-02-01},
journal = {J Diabetes Complications},
volume = {37},
number = {2},
pages = {108383},
abstract = {Deoxysphingolipids (1-deoxySLs) are neurotoxic sphingolipids associated with obesity and diabetic neuropathy (DN) and have been linked to severity of functional peripheral neuropathies. While l-serine supplementation can reduce 1-deoxySL accumulation and improve insulin sensitivity and sensory nerve velocity, long-term outcomes have not yet been examined. To assess this, we treated 2 month old db/db mice, a model of DN, with 5-20 % oral l-serine for 6 months and longitudinally quantified the extent of functional neuropathy progression. We examined putative biomarkers of neuropathy in blood and tissue and quantified levels of small fiber neuropathy, looking for associations between lowered 1-deoxySL and phenotypes. Toxic 1-deoxySLs were suppressed long-term in plasma and various tissue including the sciatic nerve, which is particularly targeted in DN. Functional neuropathy and sensory modalities were significantly improved in the treatment group well into advanced stages of disease. However, structural assessments revealed prominent axonal degeneration, apoptosis and Schwann cell pathology, suggesting that neuropathy was ongoing. Hyperglycemia and dyslipidemia persisted during our study, and high levels of glutathione were seen in the spinal cord. Our results demonstrate that despite significant functional improvements, l-serine does not prevent chronic degenerative changes specifically at the structural level, pointing to other processes such as oxidative damage and hyperglycemia, that persist despite 1-deoxySL reduction.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36865201,
title = {Developing a Phenotype Risk Score for Tic Disorders in a Large, Clinical Biobank},
author = {Tyne W Miller-Fleming and Annmarie Allos and Emily Gantz and Dongmei Yu and David A Isaacs and Carol A Mathews and Jeremiah M Scharf and Lea K Davis},
doi = {10.1101/2023.02.21.23286253},
year  = {2023},
date = {2023-02-01},
journal = {medRxiv},
abstract = {IMPORTANCE: Tics are a common feature of early-onset neurodevelopmental disorders, characterized by involuntary and repetitive movements or sounds. Despite affecting up to 2% of young children and having a genetic contribution, the underlying causes remain poorly understood, likely due to the complex phenotypic and genetic heterogeneity among affected individuals.nnOBJECTIVE: In this study, we leverage dense phenotype information from electronic health records to identify the disease features associated with tic disorders within the context of a clinical biobank. These disease features are then used to generate a phenotype risk score for tic disorder.nnDESIGN: Using de-identified electronic health records from a tertiary care center, we extracted individuals with tic disorder diagnosis codes. We performed a phenome-wide association study to identify the features enriched in tic cases versus controls (N=1,406 and 7,030; respectively). These disease features were then used to generate a phenotype risk score for tic disorder, which was applied across an independent set of 90,051 individuals. A previously curated set of tic disorder cases from an electronic health record algorithm followed by clinician chart review was used to validate the tic disorder phenotype risk score.nnMAIN OUTCOMES AND MEASURES: Phenotypic patterns associated with a tic disorder diagnosis in the electronic health record.nnRESULTS: Our tic disorder phenome-wide association study revealed 69 significantly associated phenotypes, predominantly neuropsychiatric conditions, including obsessive compulsive disorder, attention-deficit hyperactivity disorder, autism, and anxiety. The phenotype risk score constructed from these 69 phenotypes in an independent population was significantly higher among clinician-validated tic cases versus non-cases.nnCONCLUSIONS AND RELEVANCE: Our findings provide support for the use of large-scale medical databases to better understand phenotypically complex diseases, such as tic disorders. The tic disorder phenotype risk score provides a quantitative measure of disease risk that can be leveraged for the assignment of individuals in case-control studies or for additional downstream analyses.nnKEY POINTS:  Can clinical features within the electronic medical records of patients with tic disorders be used to generate a quantitative risk score that can identify other individuals at high probability of tic disorders? In this phenome-wide association study using data from electronic health records, we identify the medical phenotypes associated with a tic disorder diagnosis. We then use the resulting 69 significantly associated phenotypes, which include several neuropsychiatric comorbidities, to generate a tic disorder phenotype risk score in an independent population and validate this score with clinician-validated tic cases. The tic disorder phenotype risk score provides a computational method of evaluating and distilling the comorbidity patterns that characterize tic disorders (independent of tic diagnosis status) and may help improve downstream analyses by distinguishing between individuals that should be categorized as cases or controls for tic disorder population studies.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36806290,
title = {Multivariate genomic architecture of cortical thickness and surface area at multiple levels of analysis},
author = {Andrew D Grotzinger and Travis T Mallard and Zhaowen Liu and Jakob Seidlitz and Tian Ge and Jordan W Smoller},
doi = {10.1038/s41467-023-36605-x},
issn = {2041-1723},
year  = {2023},
date = {2023-02-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {946},
abstract = {Recent work in imaging genetics suggests high levels of genetic overlap within cortical regions for cortical thickness (CT) and surface area (SA). We model this multivariate system of genetic relationships by applying Genomic Structural Equation Modeling (Genomic SEM) and parsimoniously define five genomic brain factors underlying both CT and SA along with a general factor capturing genetic overlap across all brain regions. We validate these factors by demonstrating the generalizability of the model to a semi-independent sample and show that the factors align with biologically and functionally relevant parcellations of the cortex. We apply Stratified Genomic SEM to identify specific categories of genes (e.g., neuronal cell types) that are disproportionately associated with pleiotropy across specific subclusters of brain regions, as indexed by the genomic factors. Finally, we examine genetic associations with psychiatric and cognitive correlates, finding that broad aspects of cognitive function are associated with a general factor for SA and that psychiatric associations are null. These analyses provide key insights into the multivariate genomic architecture of two critical features of the cerebral cortex.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36732776,
title = {LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes},
author = {Abdulrahman Alasiri and Konrad J Karczewski and Brian Cole and Bao-Li Loza and Jason H Moore and Sander W van der Laan and Folkert W Asselbergs and Brendan J Keating and Jessica van Setten},
doi = {10.1186/s13040-023-00321-5},
issn = {1756-0381},
year  = {2023},
date = {2023-02-01},
journal = {BioData Min},
volume = {16},
number = {1},
pages = {3},
abstract = {BACKGROUND: Loss-of-Function (LoF) variants in human genes are important due to their impact on clinical phenotypes and frequent occurrence in the genomes of healthy individuals. The association of LoF variants with complex diseases and traits may lead to the discovery and validation of novel therapeutic targets. Current approaches predict high-confidence LoF variants without identifying the specific genes or the number of copies they affect. Moreover, there is a lack of methods for detecting knockout genes caused by compound heterozygous (CH) LoF variants.nnRESULTS: We have developed the Loss-of-Function ToolKit (LoFTK), which allows efficient and automated prediction of LoF variants from genotyped, imputed and sequenced genomes. LoFTK enables the identification of genes that are inactive in one or two copies and provides summary statistics for downstream analyses. LoFTK can identify CH LoF variants, which result in LoF genes with two copies lost. Using data from parents and offspring we show that 96% of CH LoF genes predicted by LoFTK in the offspring have the respective alleles donated by each parent.nnCONCLUSIONS: LoFTK is a command-line based tool that provides a reliable computational workflow for predicting LoF variants from genotyped and sequenced genomes, identifying genes that are inactive in 1 or 2 copies. LoFTK is an open software and is freely available to non-commercial users at https://github.com/CirculatoryHealth/LoFTK .},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37181921,
title = {Congenital Portosystemic Shunts: Variable Clinical Presentations Requiring a Tailored Endovascular or Surgical Approach},
author = {Eduardo Bent Robinson and Gregory Jordan and Danielle Katz and Shikha S Sundaram and Julia Boster and Dania Brigham and Patricia Ladd and Christine M Chan and Rebecca L Shay and Emily Ochmanek and Aparna Annam},
doi = {10.1097/PG9.0000000000000279},
issn = {2691-171X},
year  = {2023},
date = {2023-02-01},
journal = {JPGN Rep},
volume = {4},
number = {1},
pages = {e279},
abstract = {Congenital portosystemic shunts (CPSS) are rare developmental anomalies resulting in diversion of portal flow to the systemic circulation. These shunts allow intestinal blood to reach the systemic circulation directly, and if persistent or large, may lead to long-term complications. CPSS can have a variety of clinical presentations that depend on the substrate that is bypassing hepatic metabolism or the degree of hypoperfusion of the liver. Many intrahepatic shunts spontaneously close by 1 year of age, but extrahepatic and persistent intrahepatic shunts require intervention by a single session or staged closure with a multidisciplinary approach. Early detection and appropriate management are important for a good prognosis. The aim of this case series is to describe the varied clinical presentations, treatment approaches, and outcomes of 5 children with CPSS at our institution. Management of these patients should involve a multidisciplinary team, including interventional radiology, surgery, hepatology, and other medical services as the patient's clinical presentation warrants. Regardless of clinical presentation, if a CPSS persists past 1-2 years of age, closure is recommended.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36688365,
title = {Association of Depression and Poor Mental Health With Cardiovascular Disease and Suboptimal Cardiovascular Health Among Young Adults in the United States},
author = {Yaa A Kwapong and Ellen Boakye and Sadiya S Khan and Michael C Honigberg and Seth S Martin and Chigolum P Oyeka and Allison G Hays and Pradeep Natarajan and Mamas A Mamas and Roger S Blumenthal and Michael J Blaha and Garima Sharma},
doi = {10.1161/JAHA.122.028332},
issn = {2047-9980},
year  = {2023},
date = {2023-02-01},
journal = {J Am Heart Assoc},
volume = {12},
number = {3},
pages = {e028332},
abstract = {Background Depression is a nontraditional risk factor for cardiovascular disease (CVD). Data on the association of depression and poor mental health with CVD and suboptimal cardiovascular health (CVH) among young adults are limited. Methods and Results We used data from 593 616 young adults (aged 18-49 years) from the 2017 to 2020 Behavioral Risk Factor Surveillance System, a nationally representative survey of noninstitutionalized US adults. Exposures were self-reported depression and poor mental health days (PMHDs; categorized as 0, 1-13, and 14-30 days of poor mental health in the past 30 days). Outcomes were self-reported CVD (composite of myocardial infarction, angina, or stroke) and suboptimal CVH (≥2 cardiovascular risk factors: hypertension, hypercholesterolemia, overweight/obesity, smoking, diabetes, physical inactivity, and inadequate fruit and vegetable intake). Using logistic regression, we investigated the association of depression and PMHDs with CVD and suboptimal CVH, adjusting for sociodemographic factors (and cardiovascular risk factors for the CVD outcome). Of the 593 616 participants (mean age, 34.7±9.0 years), the weighted prevalence of depression was 19.6% (95% CI, 19.4-19.8), and the weighted prevalence of CVD was 2.5% (95% CI, 2.4-2.6). People with depression had higher odds of CVD than those without depression (odds ratio [OR], 2.32 [95% CI, 2.13-2.51]). There was a graded association of PMHDs with CVD. Compared with individuals with 0 PMHDs, the odds of CVD in those with 1 to 13 PMHDs and 14 to 30 PHMDs were 1.48 (95% CI, 1.34-1.62) and 2.29 (95% CI, 2.08-2.51), respectively, after adjusting for sociodemographic and cardiovascular risk factors. The associations did not differ significantly by sex or urban/rural status. Individuals with depression had higher odds of suboptimal CVH (OR, 1.79 [95% CI, 1.65-1.95]) compared with those without depression, with a similar graded relationship between PMHDs and suboptimal CVH. Conclusions Depression and poor mental health are associated with premature CVD and suboptimal CVH among young adults. Although this association is likely bidirectional, prioritizing mental health may help reduce CVD risk and improve CVH in young adults.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36865341,
title = {Development and Multi-Site External Validation of a Generalizable Risk Prediction Model for Bipolar Disorder},
author = {Colin G Walsh and Michael A Ripperger and Yirui Hu and Yi-Han Sheu and Drew Wilimitis and Amanda B Zheutlin and Daniel Rocha and Karmel W Choi and Victor M Castro and H Lester Kirchner and Christopher F Chabris and Lea K Davis and Jordan W Smoller},
doi = {10.1101/2023.02.21.23286251},
year  = {2023},
date = {2023-02-01},
journal = {medRxiv},
abstract = {Bipolar disorder is a leading contributor to disability, premature mortality, and suicide. Early identification of risk for bipolar disorder using generalizable predictive models trained on diverse cohorts around the United States could improve targeted assessment of high risk individuals, reduce misdiagnosis, and improve the allocation of limited mental health resources. This observational case-control study intended to develop and validate generalizable predictive models of bipolar disorder as part of the multisite, multinational PsycheMERGE Consortium across diverse and large biobanks with linked electronic health records (EHRs) from three academic medical centers: in the Northeast (Massachusetts General Brigham), the Mid-Atlantic (Geisinger) and the Mid-South (Vanderbilt University Medical Center). Predictive models were developed and validated with multiple algorithms at each study site: random forests, gradient boosting machines, penalized regression, including stacked ensemble learning algorithms combining them. Predictors were limited to widely available EHR-based features agnostic to a common data model including demographics, diagnostic codes, and medications. The main study outcome was bipolar disorder diagnosis as defined by the International Cohort Collection for Bipolar Disorder, 2015. In total, the study included records for 3,529,569 patients including 12,533 cases (0.3%) of bipolar disorder. After internal and external validation, algorithms demonstrated optimal performance in their respective development sites. The stacked ensemble achieved the best combination of overall discrimination (AUC = 0.82 - 0.87) and calibration performance with positive predictive values above 5% in the highest risk quantiles at all three study sites. In conclusion, generalizable predictive models of risk for bipolar disorder can be feasibly developed across diverse sites to enable precision medicine. Comparison of a range of machine learning methods indicated that an ensemble approach provides the best performance overall but required local retraining. These models will be disseminated via the PsycheMERGE Consortium website.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36778464,
title = {A panel-agnostic strategy 'HiPPo' improves diagnostic efficiency in the UK Genome Medicine Service},
author = {Eleanor G Seaby and N Simon Thomas and David Hunt and Diana Baralle and Heidi L Rehm and Anne O'Donnell-Luria and Sarah Ennis},
doi = {10.1101/2023.01.31.23285025},
year  = {2023},
date = {2023-02-01},
journal = {medRxiv},
abstract = {Genome sequencing is now available as a clinical test on the National Health Service (NHS) through the Genome Medicine Service (GMS). The GMS have set out an analytical strategy that predominantly filters genome data on a pre-selected gene panel(s). Whilst this approach reduces the number of variants requiring assessment by reporting laboratories, pathogenic variants outside of the gene panel applied may be missed, and candidate variants in novel genes are largely ignored. This study sought to compare a research exome analysis to an independent clinical genome analysis performed through the NHS for the same group of patients. When analysing the exome data, we applied a panel agnostic approach filtering for variants with  gh  athogenic  tential (HiPPo) using ClinVar, allele frequency, and  prediction tools. We then compared this gene agnostic analysis to the panel-based approach as applied by the GMS to genome data. Later we restricted HiPPo variants to a panel of the Gene Curation Coalition (GenCC) morbid genes and compared the diagnostic yield with the variants filtered using the GMS strategy. 24 patients from 8 families underwent parallel research exome sequencing and GMS genome sequencing. HiPPo analysis applied to research exome data identified a similar number of variants as the gene panel-based approach applied by the GMS. GMS clinical genome analysis identified and returned 2 pathogenic variants and 3 variants of uncertain significance. HiPPo research exome analysis identified the same variants plus an additional pathogenic variant and a further 3  variants of uncertain significance in novel genes, where case series and functional studies are underway. When HiPPo was restricted to GenCC disease genes (strong or definitive), the same pathogenic variants were identified yet statistically fewer variants required assessment to identify more diagnostic variants than reported by the GMS genome strategy. This gave a diagnostic rate per variant assessed of 20% for HiPPo restricted to GenCC versus 3% for the GMS panel-based approach. With plans to sequence 5 million more NHS patients, strategies are needed to optimise the full potential of genome data beyond gene panels whilst minimising the burden of variants that require clinical assessment.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid35981809,
title = {Improving detection of cerebral small vessel disease aetiology in patients with isolated lobar intracerebral haemorrhage},
author = {Alvin S Das and Elif Gokcal and Robert W Regenhardt and Mitchell J Horn and Kristin Schwab and Nader Daoud and Anand Viswanathan and W Taylor Kimberly and Joshua N Goldstein and Alessandro Biffi and Natalia Rost and Jonathan Rosand and Lee H Schwamm and Steven M Greenberg and M Edip Gurol},
doi = {10.1136/svn-2022-001653},
issn = {2059-8696},
year  = {2023},
date = {2023-02-01},
journal = {Stroke Vasc Neurol},
volume = {8},
number = {1},
pages = {26--33},
abstract = {BACKGROUND AND PURPOSE: We evaluate whether non-haemorrhagic imaging markers (NHIM) (white matter hyperintensity patterns, lacunes and enlarged perivascular spaces (EPVS)) can discriminate cerebral amyloid angiopathy (CAA) from hypertensive cerebral small vessel disease (HTN-cSVD) among patients with isolated lobar intracerebral haemorrhage (isolated-LICH).nnMETHODS: In patients with isolated-LICH, four cSVD aetiologic groups were created by incorporating the presence/distribution of NHIM: HTN-cSVD pattern, CAA pattern, mixed NHIM and no NHIM. CAA pattern consisted of patients with any combination of severe centrum semiovale EPVS, lobar lacunes or multiple subcortical spots pattern. HTN-cSVD pattern consisted of any HTN-cSVD markers: severe basal ganglia PVS, deep lacunes or peribasal ganglia white matter hyperintensity pattern. Mixed NHIM consisted of at least one imaging marker from either pattern. Our hypothesis was that patients with HTN-cSVD pattern/mixed NHIM would have a higher frequency of left ventricular hypertrophy (LVH), which is associated with HTN-cSVD.nnRESULTS: In 261 patients with isolated-LICH, CAA pattern was diagnosed in 93 patients, HTN-cSVD pattern in 53 patients, mixed NHIM in 19 patients and no NHIM in 96 patients. The frequency of LVH was similar among those with HTN-cSVD pattern and mixed NHIM (50% vs 39%, p=0.418) but was more frequent in HTN-cSVD pattern compared with CAA pattern (50% vs 20%, p<0.001). In a regression model, HTN-cSVD pattern (OR: 7.38; 95% CI 2.84 to 19.20) and mixed NHIM (OR: 4.45; 95% CI 1.25 to 15.90) were found to be independently associated with LVH.nnCONCLUSION: Among patients with isolated-LICH, NHIM may help differentiate HTN-cSVD from CAA, using LVH as a marker for HTN-cSVD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36601951,
title = {Embracing Heterogeneity in The Multicenter Stroke Preclinical Assessment Network (SPAN) Trial},
author = {Andreia Morais and Joseph J Locascio and Lauren H Sansing and Jessica Lamb and Karisma Nagarkatti and Takahiko Imai and Klaus van Leyen and Jaroslaw Aronowski and James I Koenig and Francesca Bosetti and Patrick Lyden and Cenk Ayata and },
doi = {10.1161/STROKEAHA.122.040638},
issn = {1524-4628},
year  = {2023},
date = {2023-02-01},
journal = {Stroke},
volume = {54},
number = {2},
pages = {620--631},
abstract = {The Stroke Preclinical Assessment Network (SPAN) is a multicenter preclinical trial platform using rodent models of transient focal cerebral ischemia to address translational failure in experimental stroke. In addition to centralized randomization and blinding and large samples, SPAN aimed to introduce heterogeneity to simulate the heterogeneity embodied in clinical trials for robust conclusions. Here, we report the heterogeneity introduced by allowing the 6 SPAN laboratories to vary most of the biological and experimental model variables and the impact of this heterogeneity on middle cerebral artery occlusion (MCAo) performance. We included the modified intention-to-treat population of the control mouse cohort of the first SPAN trial (n=421) and examined the biological and procedural independent variables and their covariance. We then determined their impact on the dependent variables cerebral blood flow drop during MCAo, time to achieve MCAo, and total anesthesia duration using multivariable analyses. We found heterogeneity in biological and procedural independent variables introduced mainly by the site. Consequently, all dependent variables also showed heterogeneity among the sites. Multivariable analyses with the site as a random effect variable revealed filament choice as an independent predictor of cerebral blood flow drop after MCAo. Comorbidity, sex, use of laser Doppler flow to monitor cerebral blood flow, days after trial onset, and maintaining anesthesia throughout the MCAo emerged as independent predictors of time to MCAo. Total anesthesia duration was predicted by most independent variables. We present with high granularity the heterogeneity introduced by the biological and model selections by the testing sites in the first trial of cerebroprotection in rodent transient filament MCAo by SPAN. Rather than trying to homogenize all variables across all sites, we embraced the heterogeneity to better approximate clinical trials. Awareness of the heterogeneity, its sources, and how it impacts the study performance may further improve the study design and statistical modeling for future multicenter preclinical trials.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36798390,
title = {A Pooled Electronic Consultation Program to Improve Access to Genetics Specialists},
author = {Emma K Folkerts and Ren E C Pelletier and Daniel C Chung and Susan A Goldstein and Douglas S Micalizzi and Kristen M Shannon and David A Sweetser and Eugene K Wong and Heidi L Rehm and Leland E Hull},
doi = {10.1101/2023.02.08.23284667},
year  = {2023},
date = {2023-02-01},
journal = {medRxiv},
abstract = {Innovative service delivery models are needed to increase access to genetics specialists. Electronic consultation (e-Consult) programs can connect clinicians with specialists. At Massachusetts General Hospital, an e-Consult service was created to address genomics-related questions. In its first year, the e-Consult service triaged 153 requests and completed 122 in an average of 3.2 days. Of the 95 e-Consults with actionable recommendations, there was documentation that most ordering clinicians followed through (82%). A variety of providers used the service, although the majority (77%) were generalists. E-Consult models should be considered as one way to increase access to genetics care.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36711707,
title = { architecture of Opa1-dependent mitochondrial cristae remodeling},
author = {Michelle Y Fry and Paula P Navarro and Xingping Qin and Zintes Inde and Virly Y Ananda and Camila Makhlouta Lugo and Pusparanee Hakim and Bridget E Luce and Yifan Ge and Julie L McDonald and Ilzat Ali and Leillani L Ha and Benjamin P Kleinstiver and David C Chan and Kristopher A Sarosiek and Luke H Chao},
doi = {10.1101/2023.01.16.524176},
year  = {2023},
date = {2023-02-01},
journal = {bioRxiv},
abstract = {Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to the lack of native 3D views of cristae morphology. We perform  cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with well-defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe elongated mitochondria with a notable stacking phenotype, as well as an absence of tubular cristae, when only l-Opa1 is present. In contrast, when mitochondria contain mainly s-Opa1, we observe irregular cristae packing, an increase in globular cristae, and decreased matrix condensation. Notably, we find the absence of l-Opa1 results in mitochondria with wider cristae junctions. BH3 profiling reveals that absence of l-Opa1 reduces cytochrome c release in response to pro-apoptotic stimuli and protects cells from apoptosis induced by anti-cancer agents. We discuss the implications Opa1-dependent cristae morphologies in cell death initiation.nnHIGHLIGHTS:  ultrastructural characterization of mitochondrial cristae with different forms of Opa1. Mitochondria with predominantly l-Opa1 show cristae stacking, longer cristae compared to WT, but also a reduction of globular cristae and no tubular cristae.Mitochondria with mostly s-Opa1 showed irregular cristae packing with wider cristae junctions and more narrow cristae than WT.BH3 profiling show Opa1-knock-out cells have reduced apoptotic priming and reduced sensitivity to apoptosis-inducing agents, and the presence l-Opa1 restores a WT protective apoptotic response.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36441169,
title = {Importance of adopting standardized MANE transcripts in clinical reporting},
author = {Caroline F Wright and David R FitzPatrick and James S Ware and Heidi L Rehm and Helen V Firth},
doi = {10.1016/j.gim.2022.10.013},
issn = {1530-0366},
year  = {2023},
date = {2023-02-01},
journal = {Genet Med},
volume = {25},
number = {2},
pages = {100331},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36602867,
title = {Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms},
author = {Jessica Cassin and Maria I Stamou and Kimberly W Keefe and Kaitlin E Sung and Celine C Bojo and Karen J Tonsfeldt and Rebecca A Rojas and Vanessa Ferreira Lopes and Lacey Plummer and Kathryn B Salnikov and David L Keefe and Metin Ozata and Myron Genel and Neoklis A Georgopoulos and Janet E Hall and William F Crowley and Stephanie B Seminara and Pamela L Mellon and Ravikumar Balasubramanian},
doi = {10.1172/jci.insight.164324},
issn = {2379-3708},
year  = {2023},
date = {2023-02-01},
journal = {JCI Insight},
volume = {8},
number = {3},
abstract = {Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36621819,
title = {Using Noncontrast Computed Tomography to Improve Prediction of Intracerebral Hemorrhage Expansion},
author = {Andrea Morotti and Gregoire Boulouis and Jawed Nawabi and Qi Li and Andreas Charidimou and Marco Pasi and Frieder Schlunk and Ashkan Shoamanesh and Aristeidis H Katsanos and Federico Mazzacane and Giorgio Busto and Francesco Arba and Laura Brancaleoni and Sebastiano Giacomozzi and Luigi Simonetti and Andrew D Warren and Michele Laudisi and Anna Cavallini and Edip M Gurol and Anand Viswanathan and Andrea Zini and Ilaria Casetta and Enrico Fainardi and Steven M Greenberg and Alessandro Padovani and Jonathan Rosand and Joshua N Goldstein},
doi = {10.1161/STROKEAHA.122.041302},
issn = {1524-4628},
year  = {2023},
date = {2023-02-01},
journal = {Stroke},
volume = {54},
number = {2},
pages = {567--574},
abstract = {BACKGROUND: Noncontrast computed tomography hypodensities are a validated predictor of hematoma expansion (HE) in intracerebral hemorrhage and a possible alternative to the computed tomography angiography (CTA) spot sign but their added value to available prediction models remains unclear. We investigated whether the inclusion of hypodensities improves prediction of HE and compared their added value over the spot sign.nnMETHODS: Retrospective analysis of patients admitted for primary spontaneous intracerebral hemorrhage at the following 8 university hospitals in Boston, US (1994-2015, prospective), Hamilton, Canada (2010-2016, retrospective), Berlin, Germany (2014-2019, retrospective), Chongqing, China (2011-2015, retrospective), Pavia, Italy (2017-2019, prospective), Ferrara, Italy (2010-2019, retrospective), Brescia, Italy (2020-2021, retrospective), and Bologna, Italy (2015-2019, retrospective). Predictors of HE (hematoma growth >6 mL and/or >33% from baseline to follow-up imaging) were explored with logistic regression. We compared the discrimination of a simple prediction model for HE based on 4 predictors (antitplatelet and anticoagulant treatment, baseline intracerebral hemorrhage volume, and onset-to-imaging time) before and after the inclusion of noncontrast computed tomography hypodensities, using receiver operating characteristic curve and De Long test for area under the curve comparison.nnRESULTS: A total of 2465 subjects were included, of whom 664 (26.9%) had HE and 1085 (44.0%) had hypodensities. Hypodensities were independently associated with HE after adjustment for confounders in logistic regression (odds ratio, 3.11 [95% CI, 2.55-3.80]; <0.001). The inclusion of noncontrast computed tomography hypodensities improved the discrimination of the 4 predictors model (area under the curve, 0.67 [95% CI, 0.64-0.69] versus 0.71 [95% CI, 0.69-0.74]; =0.025). In the subgroup of patients with a CTA available (n=895, 36.3%), the added value of hypodensities remained statistically significant (area under the curve, 0.68 [95% CI, 0.64-0.73] versus 0.74 [95% CI, 0.70-0.78]; =0.041) whereas the addition of the CTA spot sign did not provide significant discrimination improvement (area under the curve, 0.74 [95% CI, 0.70-0.78]).nnCONCLUSIONS: Noncontrast computed tomography hypodensities provided a significant added value in the prediction of HE and appear a valuable alternative to the CTA spot sign. Our findings might inform future studies and suggest the possibility to stratify the risk of HE with good discrimination without CTA.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36256779,
title = {Delineation of functionally essential protein regions for 242 neurodevelopmental genes},
author = {Sumaiya Iqbal and Tobias Brünger and Eduardo Pérez-Palma and Marie Macnee and Andreas Brunklaus and Mark J Daly and Arthur J Campbell and David Hoksza and Patrick May and Dennis Lal},
doi = {10.1093/brain/awac381},
issn = {1460-2156},
year  = {2023},
date = {2023-02-01},
journal = {Brain},
volume = {146},
number = {2},
pages = {519--533},
abstract = {Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are 'variants of uncertain significance'. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can 'tolerate' missense variants and which ones are 'essential' and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including >360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients. In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36608698,
title = {The Application of a Standard Risk Threshold for the Stratification of Maternal Morbidity among Population Subgroups},
author = {Mark A Clapp and Kaitlyn E James and Thomas H Mccoy and Roy H Perlis and Anjali J Kaimal},
doi = {10.1055/a-2008-8598},
issn = {1098-8785},
year  = {2023},
date = {2023-02-01},
journal = {Am J Perinatol},
abstract = {OBJECTIVE:  The aim of this study was to determine if a universally applied risk score threshold for severe maternal morbidity (SMM) resulted in different performance characteristics among subgroups of the population.nnSTUDY DESIGN:  This is a retrospective cohort study of deliveries that occurred between July 1, 2016, and June 30, 2020, in a single health system. We examined the performance of a validated comorbidity score to stratify SMM risk in our cohort. We considered the risk score that was associated with the highest decile of predicted risk as a "screen positive" for morbidity. We then used this same threshold to calculate the sensitivity and positive predictive value (PPV) of this "highest risk" designation among subgroups of the overall cohort based on the following characteristics: age, race/ethnicity, parity, gestational age, and planned mode of delivery.nnRESULTS:  In the overall cohort of 53,982 women, the C-statistic was 0.755 (95% confidence interval [CI], 0.741-0.769) and calibration plot demonstrated that the risk score was well calibrated. The model performed less well in the following groups: non-White or Hispanic (C-statistic, 0.734; 95% CI, 0.712-0.755), nulliparas (C-statistic, 0.735; 95% CI, 0.716-0.754), term deliveries (C-statistic, 0.712; 95% CI, 0.694-0.729), and planned vaginal delivery (C-statistic, 0.728; 95% CI, 0.709-0.747). There were differences in the PPVs by gestational age (7.8% term and 29.7% preterm) and by planned mode of delivery (8.7% vaginal and 17.7% cesarean delivery). Sensitivities were lower in women who were <35 years (36.6%), non-White or Hispanic (40.7%), nulliparous (38.9%), and those having a planned vaginal delivery (40.9%) than their counterparts.nnCONCLUSION:  The performance of a risk score for SMM can vary by population subgroups when using standard thresholds derived from the overall cohort. If applied without such considerations, such thresholds may be less likely to identify certain subgroups of the population that may be at increased risk of SMM.nnKEY POINTS: · Predictive risk models are helpful at condensing complex information into an interpretable output.. · Model performance may vary among different population subgroups.. · Prediction models should be examined for their potential to exacerbate underlying disparities..},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36778263,
title = {Correlates of symptomatic remission among individuals with post-COVID-19 condition},
author = {Roy H Perlis and Mauricio Santillana and Katherine Ognyanova and David Lazer},
doi = {10.1101/2023.01.31.23285246},
year  = {2023},
date = {2023-02-01},
journal = {medRxiv},
abstract = {IMPORTANCE: Post-COVID-19 condition (PCC), or long COVID, has become prevalent. The course of this syndrome, and likelihood of remission, has not been characterized.nnOBJECTIVE: To quantify the rates of remission of PCC, and the sociodemographic features associated with remission.nnDESIGN: 16 waves of a 50-state U.S. non-probability internet survey conducted between August 2020 and November 2022.nnSETTING: Population-based.nnPARTICIPANTS: Survey respondents age 18 and older.nnMAIN OUTCOME AND MEASURE: PCC remission, defined as reporting full recovery from COVID-19 symptoms among individuals who on a prior survey wave reported experiencing continued COVID-19 symptoms beyond 2 months after the initial month of symptoms.nnRESULTS: Among 423 survey respondents reporting continued symptoms more than 2 months after acute test-confirmed COVID-19 illness, who then completed at least 1 subsequent survey, mean age was 53.7 (SD 13.6) years; 293 (69%) identified as women, and 130 (31%) as men; 9 (2%) identified as Asian, 29 (7%) as Black, 13 (3%) as Hispanic, 15 (4%) as another category including Native American or Pacific Islander, and the remaining 357 (84%) as White. Overall, 131/423 (31%) of those who completed a subsequent survey reported no longer being symptomatic. In Cox regression models, male gender, younger age, lesser impact of PCC symptoms at initial visit, and infection when the Omicron strain predominated were all statistically significantly associated with greater likelihood of remission; presence of 'brain fog' or shortness of breath were associated with lesser likelihood of remission.nnCONCLUSIONS AND RELEVANCE: A minority of individuals reported remission of PCC symptoms, highlighting the importance of efforts to identify treatments for this syndrome or means of preventing it.nnTRIAL REGISTRATION: N/A.nnKEY POINTS:  How often do individuals with post-COVID-19 condition, or long COVID, recover fully, and what predicts this recovery? Among 423 individuals who initially reported post-COVID-19 condition and completed at least one subsequent survey, 131 (31%) later described symptomatic remission. Younger age, male gender, lesser symptom severity at initial survey, and infection during Omicron-predominance were associated with greater likelihood of reporting recovery. A minority of people with post-COVID-19 condition report spontaneous remission of symptoms, highlighting the importance of developing treatments for this syndrome.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid35899434,
title = {Socioeconomic changes predict genome-wide DNA methylation in childhood},
author = {Jiaxuan Liu and Janine Cerutti and Alexandre A Lussier and Yiwen Zhu and Brooke J Smith and Andrew D A C Smith and Erin C Dunn},
doi = {10.1093/hmg/ddac171},
issn = {1460-2083},
year  = {2023},
date = {2023-02-01},
journal = {Hum Mol Genet},
volume = {32},
number = {5},
pages = {709--719},
abstract = {Childhood socioeconomic position (SEP) is a major determinant of health and well-being across the entire life course. To effectively prevent and reduce health risks related to SEP, it is critical to better understand when and under what circumstances socioeconomic adversity shapes biological processes. DNA methylation (DNAm) is one such mechanism for how early life adversity 'gets under the skin'. In this study, we evaluated the dynamic relationship between SEP and DNAm across childhood using data from 946 mother-child pairs in the Avon Longitudinal Study of Parents and Children. We assessed six SEP indicators spanning financial, occupational and residential domains during very early childhood (ages 0-2), early childhood (ages 3-5) and middle childhood (ages 6-7). Epigenome-wide DNAm was measured at 412 956 cytosine-guanines (CpGs) from peripheral blood at age 7. Using an innovative two-stage structured life-course modeling approach, we tested three life-course hypotheses for how SEP shapes DNAm profiles-accumulation, sensitive period and mobility. We showed that changes in the socioeconomic environment were associated with the greatest differences in DNAm, and that middle childhood may be a potential sensitive period when socioeconomic instability is especially important in shaping DNAm. Top SEP-related DNAm CpGs were overrepresented in genes involved in pathways important for neural development, immune function and metabolic processes. Our findings highlight the importance of socioeconomic stability during childhood and if replicated, may emphasize the need for public programs to help children and families experiencing socioeconomic instability and other forms of socioeconomic adversity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36426646,
title = {Validation of a predictive model for obstructive sleep apnea in people with Down syndrome},
author = {Brian G Skotko and Alexandra Garza Flores and Ibrahim Elsharkawi and Vasiliki Patsiogiannis and Mary Ellen McDonough and Damiano Verda and Marco Muselli and Roberto Hornero and David Gozal and Eric A Macklin},
doi = {10.1002/ajmg.a.63055},
issn = {1552-4833},
year  = {2023},
date = {2023-02-01},
journal = {Am J Med Genet A},
volume = {191},
number = {2},
pages = {518--525},
abstract = {Detecting obstructive sleep apnea (OSA) is important to both prevent significant comorbidities in people with Down syndrome (DS) and untangle contributions to other behavioral and mental health diagnoses. However, laboratory-based polysomnograms are often poorly tolerated, unavailable, or not covered by health insurance for this population. In previous work, our team developed a prediction model that seemed to hold promise in identifying which people with DS might not have significant apnea and, consequently, might be able to forgo a diagnostic polysomnogram. In this study, we sought to validate these findings in a novel set of participants with DS. We recruited an additional 64 participants with DS, ages 3-35 years. Caregivers completed the same validated questionnaires, and our study team collected vital signs, physical exam findings, and medical histories that were previously shown to be predictive. Patients then had a laboratory-based polysomnogram. The best modeling had a validated negative predictive value of 50% for an apnea-hypopnea index (AHI) > 1/hTST and 73.7% for AHI >5/hTST. The positive predictive values were 60% and 39.1%, respectively. As such, a clinically reliable screening tool for OSA in people with DS was not achieved. Patients with DS should continue to be monitored for OSA according to current healthcare guidelines.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36539061,
title = {Best practices to reduce COVID-19 in group homes for individuals with serious mental illness and intellectual and developmental disabilities: Protocol for a hybrid type 1 effectiveness-implementation cluster randomized trial},
author = {Julie H Levison and David Krane and Karen Donelan and Kelly Aschbrenner and Hao D Trieu and Cindy Chau and Anna Wilson and Nicolas M Oreskovic and Kelly Irwin and Lisa I Iezzoni and Haiyi Xie and Ronita Samuels and Paula Silverman and Joey Batson and Ahmed Fathi and Stefanie Gamse and Sibyl Holland and Jessica Wolfe and Kim Shellenberger and Elizabeth Cella and Bruce Bird and Brian G Skotko and Stephen Bartels},
doi = {10.1016/j.cct.2022.107053},
issn = {1559-2030},
year  = {2023},
date = {2023-02-01},
journal = {Contemp Clin Trials},
volume = {125},
pages = {107053},
abstract = {BACKGROUND: People with serious mental illness (SMI) and intellectual disabilities and/or developmental disabilities (ID/DD) living in group homes (GHs) and residential staff are at higher risk for COVID-19 infection, hospitalization, and death compared with the general population.nnMETHODS: We describe a hybrid type 1 effectiveness-implementation cluster randomized trial to assess evidence-based infection prevention practices to prevent COVID-19 for residents with SMI or ID/DD and the staff in GHs. The trial will use a cluster randomized design in 400 state-funded GHs in Massachusetts for adults with SMI or ID/DD to compare effectiveness and implementation of "Tailored Best Practices" (TBP) consisting of evidence-based COVID-19 infection prevention practices adapted for residents with SMI and ID/DD and GH staff; to "General Best Practices" (GBP), consisting of required standard of care reflecting state and federal standard general guidelines for COVID-19 prevention in GHs. External (i.e., community-based research staff) and internal (i.e., GH staff leadership) personnel will facilitate implementation of TBP. The primary effectiveness outcome is incident SARS-CoV-2 infection and secondary effectiveness outcomes include COVID-19-related hospitalizations and mortality in GHs. The primary implementation outcomes are fidelity to TBP and rates of COVID-19 vaccination. Secondary implementation outcomes are adoption, adaptation, reach, and maintenance. Outcomes will be assessed at baseline, 3-, 6-, 9-, 12-, and 15-months post-randomization.nnCONCLUSIONS: This study will advance knowledge on comparative effectiveness and implementation of two different strategies to prevent COVID-19-related infection, morbidity, and mortality and promote fidelity and adoption of these interventions in high-risk GHs for residents with SMI or ID/DD and staff.nnCLINICAL TRIAL REGISTRATION NUMBER: NCT04726371.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36739343,
title = {Interpreting variants in genes affected by clonal hematopoiesis in population data},
author = {Sanna Gudmundsson and Colleen M Carlston and Anne O'Donnell-Luria},
doi = {10.1007/s00439-023-02526-4},
issn = {1432-1203},
year  = {2023},
date = {2023-02-01},
journal = {Hum Genet},
abstract = {Reference population databases like the Genome Aggregation Database (gnomAD) have improved our ability to interpret the human genome. Variant frequencies and frequency-derived tools (such as depletion scores) have become fundamental to variant interpretation and the assessment of variant-gene-disease relationships. Clonal hematopoiesis (CH) obstructs variant interpretation as somatic variants that provide proliferative advantage will affect variant frequencies, depletion scores, and downstream filtering. Further, default filtering of variants or genes associated with CH risks filtering bona fide germline variants as variants associated with CH can also cause Mendelian conditions. Here, we provide our insights on interpreting population variant data in genes affected by clonal hematopoiesis, as well as recommendations for careful review of 36 established CH genes associated with neurodevelopmental conditions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36790806,
title = {Association of Post-COVID-19 Condition Symptoms and Employment Status},
author = {Roy H Perlis and Kristin Lunz Trujillo and Alauna Safarpour and Mauricio Santillana and Katherine Ognyanova and James Druckman and David Lazer},
doi = {10.1001/jamanetworkopen.2022.56152},
issn = {2574-3805},
year  = {2023},
date = {2023-02-01},
journal = {JAMA Netw Open},
volume = {6},
number = {2},
pages = {e2256152},
abstract = {IMPORTANCE: Little is known about the functional correlates of post-COVID-19 condition (PCC), also known as long COVID, particularly the relevance of neurocognitive symptoms.nnOBJECTIVE: To characterize prevalence of unemployment among individuals who did, or did not, develop PCC after acute infection.nnDESIGN, SETTING, AND PARTICIPANTS: This survey study used data from 8 waves of a 50-state US nonprobability internet population-based survey of respondents aged 18 to 69 years conducted between February 2021 and July 2022.nnMAIN OUTCOMES AND MEASURES: The primary outcomes were self-reported current employment status and the presence of PCC, defined as report of continued symptoms at least 2 months beyond initial month of symptoms confirmed by a positive COVID-19 test.nnRESULTS: The cohort included 15 308 survey respondents with test-confirmed COVID-19 at least 2 months prior, of whom 2236 (14.6%) reported PCC symptoms, including 1027 of 2236 (45.9%) reporting either brain fog or impaired memory. The mean (SD) age was 38.8 (13.5) years; 9679 respondents (63.2%) identified as women and 10 720 (70.0%) were White. Overall, 1418 of 15 308 respondents (9.3%) reported being unemployed, including 276 of 2236 (12.3%) of those with PCC and 1142 of 13 071 (8.7%) of those without PCC; 8229 respondents (53.8%) worked full-time, including 1017 (45.5%) of those with PCC and 7212 (55.2%) without PCC. In survey-weighted regression models excluding retired respondents, the presence of PCC was associated with a lower likelihood of working full-time (odds ratio [OR], 0.71 [95% CI, 0.63-0.80]; adjusted OR, 0.84 [95% CI, 0.74-0.96]) and with a higher likelihood of being unemployed (OR, 1.45 [95% CI, 1.22-1.73]; adjusted OR, 1.23 [95% CI, 1.02-1.48]). The presence of any cognitive symptom was associated with lower likelihood of working full time (OR, 0.70 [95% CI, 0.56-0.88]; adjusted OR, 0.75 [95% CI, 0.59-0.84]).nnCONCLUSIONS AND RELEVANCE: PCC was associated with a greater likelihood of unemployment and lesser likelihood of working full time in adjusted models. The presence of cognitive symptoms was associated with diminished likelihood of working full time. These results underscore the importance of developing strategies to treat and manage PCC symptoms.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37077322,
title = {Peak width of skeletonized mean diffusivity and cognitive performance in cerebral amyloid angiopathy},
author = {Mitchell J Horn and Elif Gokcal and J Alex Becker and Alvin S Das and Kristin Schwab and Maria Clara Zanon Zotin and Joshua N Goldstein and Jonathan Rosand and Anand Viswanathan and Jonathan R Polimeni and Marco Duering and Steven M Greenberg and M Edip Gurol},
doi = {10.3389/fnins.2023.1141007},
issn = {1662-4548},
year  = {2023},
date = {2023-01-01},
journal = {Front Neurosci},
volume = {17},
pages = {1141007},
abstract = {BACKGROUND: Cerebral Amyloid Angiopathy (CAA) is a cerebral small vessel disease that can lead to microstructural disruption of white matter (WM), which can be measured by the Peak Width of Skeletonized Mean Diffusivity (PSMD). We hypothesized that PSMD measures would be increased in patients with CAA compared to healthy controls (HC), and increased PSMD is associated with lower cognitive scores in patients with CAA.nnMETHODS: Eighty-one probable CAA patients without cognitive impairment who were diagnosed with Boston criteria and 23 HCs were included. All subjects underwent an advanced brain MRI with high-resolution diffusion-weighted imaging (DWI). PSMD scores were quantified from a probabilistic skeleton of the WM tracts in the mean diffusivity (MD) image using a combination of fractional anisotropy (FA) and the FSL Tract-Based Spatial Statistics (TBSS) algorithm (www.psmd-marker.com). Within CAA cohort, standardized z-scores of processing speed, executive functioning and memory were obtained.nnRESULTS: The mean of age and sex were similar between CAA patients (69.6 ± 7.3, 59.3% male) and HCs (70.6 ± 8.5, 56.5% male) ( = 0.581 and  = 0.814). PSMD was higher in the CAA group [(4.13 ± 0.94) × 10 mm/s] compared to HCs [(3.28 ± 0.51) × 10 mm/s] ( < 0.001). In a linear regression model corrected for relevant variables, diagnosis of CAA was independently associated with increased PSMD compared to HCs ( = 0.45, 95% CI 0.13-0.76,  = 0.006). Within CAA cohort, higher PSMD was associated with lower scores in processing speed ( < 0.001), executive functioning ( = 0.004), and memory (0.047). Finally, PSMD outperformed all other MRI markers of CAA by explaining most of the variance in models predicting lower scores in each cognitive domain.nnDISCUSSION: Peak Width of Skeletonized Mean Diffusivity is increased in CAA, and it is associated with worse cognitive scores supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA. As a robust marker, PSMD can be used in clinical trials or practice.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36693822,
title = {Polygenic risk for mental disorders as predictors of posttraumatic stress disorder after mild traumatic brain injury},
author = {Murray B Stein and Sonia Jain and Livia Parodi and Karmel W Choi and Adam X Maihofer and Lindsay D Nelson and Pratik Mukherjee and Xiaoying Sun and Feng He and David O Okonkwo and Joseph T Giacino and Frederick K Korley and Mary J Vassar and Claudia S Robertson and Michael A McCrea and Nancy Temkin and Amy J Markowitz and Ramon Diaz-Arrastia and Jonathan Rosand and Geoffrey T Manley and },
doi = {10.1038/s41398-023-02313-9},
issn = {2158-3188},
year  = {2023},
date = {2023-01-01},
journal = {Transl Psychiatry},
volume = {13},
number = {1},
pages = {24},
abstract = {Many patients with mild traumatic brain injury (mTBI) are at risk for mental health problems such as posttraumatic stress disorder (PTSD). The objective of this study was to determine whether the polygenic risk for PTSD (or for related mental health disorders or traits including major depressive disorder [MDD] and neuroticism [NEU]) was associated with an increased likelihood of PTSD in the aftermath of mTBI. We used data from individuals of European ancestry with mTBI enrolled in TRACK-TBI (n = 714), a prospective longitudinal study of level 1 trauma center patients. One hundred and sixteen mTBI patients (16.3%) had probable PTSD (PCL-5 score ≥33) at 6 months post-injury. We used summary statistics from recent GWAS studies of PTSD, MDD, and NEU to generate polygenic risk scores (PRS) for individuals in our sample. A multivariable model that included age, sex, pre-injury history of mental disorder, and cause of injury explained 7% of the variance in the PTSD outcome; the addition of the PTSD-PRS (and five ancestral principal components) significantly increased the variance explained to 11%. The adjusted odds of PTSD in the uppermost PTSD-PRS quintile was nearly four times higher (aOR = 3.71, 95% CI 1.80-7.65) than in the lowest PTSD-PRS quintile. There was no evidence of a statistically significant interaction between PTSD-PRS and prior history of mental disorder, indicating that PTSD-PRS had similar predictive utility among those with and without pre-injury psychiatric illness. When added to the model, neither MDD-PRS nor NEU-PRS were significantly associated with the PTSD outcome. These findings show that the risk for PTSD in the context of mTBI is, in part, genetically influenced. They also raise the possibility that an individual's PRS could be clinically actionable if used-possibly with other non-genetic predictors-to signal the need for enhanced follow-up and early intervention; this precision medicine approach needs to be prospectively studied.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36653560,
title = {Mono- and biallelic variant effects on disease at biobank scale},
author = {H O Heyne and J Karjalainen and K J Karczewski and S M Lemmelä and W Zhou and  and A S Havulinna and M Kurki and H L Rehm and A Palotie and M J Daly},
doi = {10.1038/s41586-022-05420-7},
issn = {1476-4687},
year  = {2023},
date = {2023-01-01},
journal = {Nature},
volume = {613},
number = {7944},
pages = {519--525},
abstract = {Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance. Here we examine the homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36873109,
title = {Co-occurring pathogenic variants in 6q27 associated with dementia spectrum disorders in a Peruvian family},
author = {Karla Lucia F Alvarez and Jorge Alberto Aguilar-Pineda and Michelle M Ortiz-Manrique and Marluve F Paredes-Calderon and Bryan C Cardenas-Quispe and Karin Jannet Vera-Lopez and Luis D Goyzueta-Mamani and Miguel Angel Chavez-Fumagalli and Gonzalo Davila-Del-Carpio and Antero Peralta-Mestas and Patricia L Musolino and Christian Lacks Lino Cardenas},
doi = {10.3389/fnmol.2023.1104585},
issn = {1662-5099},
year  = {2023},
date = {2023-01-01},
journal = {Front Mol Neurosci},
volume = {16},
pages = {1104585},
abstract = {Evidence suggests that there may be racial differences in risk factors associated with the development of Alzheimer's disease and related dementia (ADRD). We used whole-genome sequencing analysis and identified a novel combination of three pathogenic variants in the heterozygous state (: rs7739897 and : rs61740334; rs3800544) in a Peruvian family with a strong clinical history of ADRD. Notably, the combination of these variants was present in two generations of affected individuals but absent in healthy members of the family.  and  studies have provided insights into the pathogenicity of these variants. These studies predict that the loss of function of the mutant UNC93A and WDR27 proteins induced dramatic changes in the global transcriptomic signature of brain cells, including neurons, astrocytes, and especially pericytes and vascular smooth muscle cells, indicating that the combination of these three variants may affect the neurovascular unit. In addition, known key molecular pathways associated with dementia spectrum disorders were enriched in brain cells with low levels of UNC93A and WDR27. Our findings have thus identified a genetic risk factor for familial dementia in a Peruvian family with an Amerindian ancestral background.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36998779,
title = {How often is occult atrial fibrillation in cryptogenic stroke causal vs. incidental? A meta-analysis},
author = {Napasri Chaisinanunkul and Shaan Khurshid and Brian H Buck and Alejandro A Rabinstein and Christopher D Anderson and Michael D Hill and Jennifer E Fugate and Jeffrey L Saver},
doi = {10.3389/fneur.2023.1103664},
issn = {1664-2295},
year  = {2023},
date = {2023-01-01},
journal = {Front Neurol},
volume = {14},
pages = {1103664},
abstract = {INTRODUCTION: Long-term cardiac monitoring studies have unveiled low-burden, occult atrial fibrillation (AF) in some patients with otherwise cryptogenic stroke (CS), but occult AF is also found in some individuals without a stroke history and in patients with stroke of a known cause (KS). Clinical management would be aided by estimates of how often occult AF in a patient with CS is causal vs. incidental.nnMETHODS: Through a systematic search, we identified all case-control and cohort studies applying identical long-term monitoring techniques to both patients with CS and KS. We performed a random-effects meta-analysis across these studies to determine the best estimate of the differential frequency of occult AF in CS and KS among all patients and across age subgroups. We then applied Bayes' theorem to determine the probability that occult AF is causal or incidental.nnRESULTS: The systematic search identified three case-control and cohort studies enrolling 560 patients (315 CS, 245 KS). Methods of long-term monitoring were implantable loop recorder in 31.0%, extended external monitoring in 67.9%, and both in 1.2%. Crude cumulative rates of AF detection were CS 47/315 (14.9%) vs. KS 23/246 (9.3%). In the formal meta-analysis, the summary odds ratio for occult AF in CS vs. KS in all patients was 1.80 (95% CI, 1.05-3.07),  = 0.03. With the application of Bayes' theorem, the corresponding probabilities indicated that, when present, occult AF in patients with CS is causal in 38.2% (95% CI, 0-63.6%) of patients. Analyses stratified by age suggested that detected occult AF in patients with CS was causal in 62.3% (95 CI, 0-87.1%) of patients under the age of 65 years and 28.5% (95 CI, 0-63.7%) of patients aged 65 years and older but estimates had limited precision.nnCONCLUSION: Current evidence is preliminary, but it indicates that in cryptogenic stroke when occult AF is found, it is causal in about 38.2% of patients. These findings suggest that anticoagulation therapy may be beneficial to prevent recurrent stroke in a substantial proportion of patients with CS found to have occult AF.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36653343,
title = {Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure},
author = {Joel T Rämö and Tuomo Kiiskinen and Richard Seist and Kristi Krebs and Masahiro Kanai and Juha Karjalainen and Mitja Kurki and Eija Hämäläinen and Paavo Häppölä and Aki S Havulinna and Heidi Hautakangas and  and Reedik Mägi and Priit Palta and Tõnu Esko and Andres Metspalu and Matti Pirinen and Konrad J Karczewski and Samuli Ripatti and Lili Milani and Konstantina M Stankovic and Antti Mäkitie and Mark J Daly and Aarno Palotie},
doi = {10.1038/s41467-022-32936-3},
issn = {2041-1723},
year  = {2023},
date = {2023-01-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {157},
abstract = {Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 3504 cases and 861,198 controls. We identify 23 novel risk loci (p < 5 × 10) and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7). We demonstrate developmental stage-dependent immunostaining patterns of MEPE and RUNX2 in mouse otic capsules. In most association loci, the nearest protein-coding genes are implicated in bone remodelling, mineralization or severe skeletal disorders. We highlight multiple genes involved in transforming growth factor beta signalling for follow-up studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37481995,
title = {3-deazaadenosine: A promising novel p38γ antagonist with potential as a breast cancer therapeutic agent},
author = {Pradeep Natarajan and Munikumar Manne and Swetha Kumari Koduru and Teja Sree Bokkasam},
doi = {10.1016/j.ctarc.2023.100744},
issn = {2468-2942},
year  = {2023},
date = {2023-01-01},
journal = {Cancer Treat Res Commun},
volume = {36},
pages = {100744},
abstract = {Human p38γ protein kinase, or MAPK12, is a crucial signaling protein that is important in channelizing membrane signals to the nucleus in the MAPK cascade pathway, associated with breast and colorectal cancer, besides other forms of malignancies and atherosclerotic lesions too. P38γ has a significant contribution to the progression of breast carcinoma due to its multifaceted functions. Targeting p38γ for defining potent antagonists against p38γ can turn out to be an attractive and novel means of breast cancer therapeutics. Novel and potent lead molecules were designed utilizing computational drug design methodologies. Using high-throughput virtual screening, 1909 geometrically similar analogs of known inhibitors were generated, primarily using BIRB796, SB202190, ANP, CHEBI: 620708, and CHEBI: 524699. Chemical correctness was ensured using LigPrep for the standalone library, and Prep Wizard for p38γ using Maestro v.11.5. Using the Glide v5.5 flexible docking procedure on a standalone library of p38γ binding sites, we defined 18 potential leads and assessed their ADMET properties. Lead "1", among the proposed four p38γ antagonists with high-scoring and favorable interactions, was considered for 100 ns molecular dynamics simulations. Among the four proposed leads, Lead '1' displayed consistent and stable bonding interactions with p38γ throughout the 100 ns molecular dynamics (MD) simulations. Additionally, it formed water bridges, contributing to its strong association with the protein. Notably, Lead '1' (3-deazaadenosine) exhibited favorable root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) within the acceptable range of pharmacological properties. Thus, 3-deazaadenosine and its mimetic might be promising new directions for developing a novel class of antagonists for breast cancer treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36624503,
title = {Continuing a search for a diagnosis: the impact of adolescence and family dynamics},
author = {Ilana M Miller and Beverly M Yashar and  and Ellen F Macnamara},
doi = {10.1186/s13023-022-02598-x},
issn = {1750-1172},
year  = {2023},
date = {2023-01-01},
journal = {Orphanet J Rare Dis},
volume = {18},
number = {1},
pages = {6},
abstract = {The "diagnostic odyssey" describes the process those with undiagnosed conditions undergo to identify a diagnosis. Throughout this process, families of children with undiagnosed conditions have multiple opportunities to decide whether to continue or stop their search for a diagnosis and accept the lack of a diagnostic label. Previous studies identified factors motivating a family to begin searching, but there is limited information about the decision-making process in a prolonged search and how the affected child impacts a family's decision. This study aimed to understand how families of children with undiagnosed diseases decide whether to continue to pursue a diagnosis after standard clinical testing has failed. Parents who applied to the Undiagnosed Disease Network (UDN) at the National Institutes of Health (NIH) were recruited to participate in semi-structured interviews. The 2015 Supportive Care Needs model by Pelenstov, which defines critical needs in families with rare/undiagnosed diseases, provided a framework for interview guide development and transcript analysis (Pelentsov et al in Disabil Health J 8(4):475-491, 2015. https://doi.org/10.1016/J.DHJO.2015.03.009 ). A deductive, iterative coding approach was used to identify common unifying themes. Fourteen parents from 13 families were interviewed. The average child's age was 11 years (range 3-18) and an average 63% of their life had been spent searching for a diagnosis. Our analysis found that alignment or misalignment of parent and child needs impact the trajectory of the diagnostic search. When needs and desires align, reevaluation of a decision to pursue a diagnosis is limited. However, when there is conflict between parent and child desires, there is reevaluation, and often a pause, in the search. This tension is exacerbated when children are adolescents and attempting to balance their dependence on parents for medical care with a natural desire for independence. Our results provide novel insights into the roles of adolescents in the diagnostic odyssey. The tension between desired and realistic developmental outcomes for parents and adolescents impacts if, and how, the search for a diagnosis progresses.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36028773,
title = {Genetics of circadian rhythms and sleep in human health and disease},
author = {Jacqueline M Lane and Jingyi Qian and Emmanuel Mignot and Susan Redline and Frank A J L Scheer and Richa Saxena},
doi = {10.1038/s41576-022-00519-z},
issn = {1471-0064},
year  = {2023},
date = {2023-01-01},
journal = {Nat Rev Genet},
volume = {24},
number = {1},
pages = {4--20},
abstract = {Circadian rhythms and sleep are fundamental biological processes integral to human health. Their disruption is associated with detrimental physiological consequences, including cognitive, metabolic, cardiovascular and immunological dysfunctions. Yet many of the molecular underpinnings of sleep regulation in health and disease have remained elusive. Given the moderate heritability of circadian and sleep traits, genetics offers an opportunity that complements insights from model organism studies to advance our fundamental molecular understanding of human circadian and sleep physiology and linked chronic disease biology. Here, we review recent discoveries of the genetics of circadian and sleep physiology and disorders with a focus on those that reveal causal contributions to complex diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36564505,
title = {Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies},
author = {Xihao Li and Corbin Quick and Hufeng Zhou and Sheila M Gaynor and Yaowu Liu and Han Chen and Margaret Sunitha Selvaraj and Ryan Sun and Rounak Dey and Donna K Arnett and Lawrence F Bielak and Joshua C Bis and John Blangero and Eric Boerwinkle and Donald W Bowden and Jennifer A Brody and Brian E Cade and Adolfo Correa and L Adrienne Cupples and Joanne E Curran and Paul S de Vries and Ravindranath Duggirala and Barry I Freedman and Harald H H Göring and Xiuqing Guo and Jeffrey Haessler and Rita R Kalyani and Charles Kooperberg and Brian G Kral and Leslie A Lange and Ani Manichaikul and Lisa W Martin and Stephen T McGarvey and Braxton D Mitchell and May E Montasser and Alanna C Morrison and Take Naseri and Jeffrey R O'Connell and Nicholette D Palmer and Patricia A Peyser and Bruce M Psaty and Laura M Raffield and Susan Redline and Alexander P Reiner and Muagututi'a Sefuiva Reupena and Kenneth M Rice and Stephen S Rich and Colleen M Sitlani and Jennifer A Smith and Kent D Taylor and Ramachandran S Vasan and Cristen J Willer and James G Wilson and Lisa R Yanek and Wei Zhao and  and Jerome I Rotter and Pradeep Natarajan and Gina M Peloso and Zilin Li and Xihong Lin},
doi = {10.1038/s41588-022-01225-6},
issn = {1546-1718},
year  = {2023},
date = {2023-01-01},
journal = {Nat Genet},
volume = {55},
number = {1},
pages = {154--164},
abstract = {Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36658419,
title = {Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death},
author = {Alicia B Byrne and Peer Arts and Thuong T Ha and Karin S Kassahn and Lynn S Pais and Anne O'Donnell-Luria and  and Milena Babic and Mahalia S B Frank and Jinghua Feng and Paul Wang and David M Lawrence and Leila Eshraghi and Luis Arriola and John Toubia and Hung Nguyen and  and George McGillivray and Jason Pinner and Fiona McKenzie and Rebecca Morrow and Jill Lipsett and Nick Manton and T Yee Khong and Lynette Moore and Jan E Liebelt and Andreas W Schreiber and Sarah L King-Smith and Tristan S E Hardy and Matilda R Jackson and Christopher P Barnett and Hamish S Scott},
doi = {10.1038/s41591-022-02142-1},
issn = {1546-170X},
year  = {2023},
date = {2023-01-01},
journal = {Nat Med},
volume = {29},
number = {1},
pages = {180--189},
abstract = {Pregnancy loss and perinatal death are devastating events for families. We assessed 'genomic autopsy' as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known genetic disorders and identifies novel phenotypes and disease genes. Inheritance of 42% of definitive diagnoses were either autosomal recessive (30.8%), X-linked recessive (3.8%) or autosomal dominant (excluding de novos, 7.7%), with risk of recurrence in future pregnancies. We report that at least ten families (5%) used their diagnosis for preimplantation (5) or prenatal diagnosis (5) of 12 pregnancies. We emphasize the clinical importance of genomic investigations of pregnancy loss and perinatal death, with short turnaround times for diagnostic reporting and followed by systematic research follow-up investigations. This approach has the potential to enable accurate counseling for future pregnancies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36321455,
title = {Blood Pressure Control Targets and Risk of Cardiovascular and Cerebrovascular Events After Intracerebral Hemorrhage},
author = {Kay-Cheong Teo and Sophia Keins and Jessica R Abramson and William C Y Leung and Ian Y H Leung and Yuen-Kwun Wong and Charming Yeung and Christina Kourkoulis and Andrew D Warren and Koon-Ho Chan and Raymond T F Cheung and Shu-Leong Ho and M Edip Gurol and Anand Viswanathan and Steven M Greenberg and Christopher D Anderson and Kui-Kai Lau and Jonathan Rosand and Alessandro Biffi},
doi = {10.1161/STROKEAHA.122.039709},
issn = {1524-4628},
year  = {2023},
date = {2023-01-01},
journal = {Stroke},
volume = {54},
number = {1},
pages = {78--86},
abstract = {BACKGROUND: Intracerebral hemorrhage (ICH) survivors are at high risk for recurrent stroke and cardiovascular events. Blood pressure (BP) control represents the most potent intervention to lower these risks, but optimal treatment targets in this patient population remain unknown. We sought to determine whether survivors of ICH achieving more intensive BP control than current guideline recommendations (systolic BP <130 mmHg and diastolic BP <80 mmHg) were at lower risk of major adverse cardiovascular and cerebrovascular events and mortality.nnMETHODS: We analyzed data for 1828 survivors of spontaneous ICH from 2 cohort studies. Follow-up BP measurements were recorded 3 and 6 months after ICH, and every 6 months thereafter. Outcomes of interest were major adverse cardiovascular and cerebrovascular events (recurrent ICH, incident ischemic stroke, myocardial infarction), vascular mortality (defined as mortality attributed to recurrent ICH, ischemic stroke, or myocardial infarction), and all-cause mortality.nnRESULTS: During a median follow-up of 46.2 months, we observed 166 recurrent ICH, 68 ischemic strokes, 69 myocardial infarction, and 429 deaths. Compared with survivors of ICH with systolic BP 120 to 129 mmHg, participants who achieved systolic BP <120 mmHg displayed reduced risk of recurrent ICH (adjusted hazard ratio [AHR], 0.74 [95% CI, 0.59-0.94]) and major adverse cardiovascular and cerebrovascular events (AHR, 0.69 [95% CI, 0.53-0.92]). All-cause mortality (AHR, 0.76 [95% CI, 0.57-1.03]) and vascular mortality (AHR, 0.68 [95% CI, 0.45-1.01]) did not differ significantly. Among participants aged >75 years or with modified Rankin Scale score 4 to 5, systolic BP <120 mmHg was associated with increased all-cause mortality (AHR, 1.38 [95% CI, 1.02-1.85] and AHR, 1.36 [95% CI, 1.03-1.78], respectively), but not vascular mortality. We found no differences in outcome rates between survivors of ICH with diastolic BP <70 versus 70 to 79 mmHg.nnCONCLUSIONS: Targeting systolic BP <120 mmHg in select groups of survivors of ICH could result in decreased major adverse cardiovascular and cerebrovascular events risk without increasing mortality. Our findings warrant investigation in dedicated randomized controlled trials.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36314243,
title = {Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting  in Nonhuman Primate and Mouse Models},
author = {Richard G Lee and Anne Marie Mazzola and Maurine C Braun and Colin Platt and Scott B Vafai and Sekar Kathiresan and Ellen Rohde and Andrew M Bellinger and Amit V Khera},
doi = {10.1161/CIRCULATIONAHA.122.062132},
issn = {1524-4539},
year  = {2023},
date = {2023-01-01},
journal = {Circulation},
volume = {147},
number = {3},
pages = {242--253},
abstract = {BACKGROUND: VERVE-101 is an investigational in vivo CRISPR base-editing medicine designed to alter a single DNA base in the  gene, permanently turn off hepatic protein production, and thereby durably lower low-density lipoprotein cholesterol. We test the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of nonhuman primates and a murine F1 progeny study.nnMETHODS: Cynomolgus monkeys were given a single intravenous infusion of a vehicle control (n=10) or VERVE-101 at a dose of 0.75 mg/kg (n=4) or 1.5 mg/kg (n=22) with subsequent follow-up up to 476 days. Two studies assessed the potential for germline editing, including sequencing sperm samples from sexually mature male nonhuman primates treated with VERVE-101 and genotyping offspring from female mice treated with the murine surrogate of VERVE-101 (VERVE-101mu).nnRESULTS: Liver biopsies 14 days after dosing noted mean  editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg, respectively. This translated into mean reductions in blood PCSK9 (proprotein convertase subtilisin/kexin type 9) of 67% and 83% and reductions of low-density lipoprotein cholesterol of 49% and 69% at the 0.75 and 1.5 mg/kg doses, respectively, assessed as time-weighted average change from baseline between day 28 and up to 476 days after dosing. Liver safety monitoring noted a transient rise in alanine aminotransferase and aspartate aminotransferase concentrations after infusion that fully resolved by day 14 with no accompanying change in total bilirubin. In a subset of monkeys necropsied 1 year after dosing, no findings related to VERVE-101 were identified on macroscopic and histopathologic assessment of the liver and other organs. In the study to assess potential germline editing of male nonhuman primates, sperm samples collected after VERVE-101 dosing showed no evidence of  editing. Among 436 offspring of female mice treated with a saturating dose of VERVE-101mu, the  edit was transmitted in 0 of 436 animals.nnCONCLUSIONS: VERVE-101 was well tolerated in nonhuman primates and led to 83% lower blood PCSK9 protein and 69% lower low-density lipoprotein cholesterol with durable effects up to 476 days after dosing. These results have supported the initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37179546,
title = {Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease},
author = {Antti Tallgren and Leo Kager and Gina O'Grady and Hannu Tuominen and Jarmo Körkkö and Outi Kuismin and Martha Feucht and Callum Wilson and Jana Behunova and Eleina England and Mitja I Kurki and Aarno Palotie and Mikko Hallman and Riitta Kaarteenaho and Franco Laccone and Kaan Boztug and Reetta Hinttala and Johanna Uusimaa},
doi = {10.3389/fnins.2023.1123327},
issn = {1662-4548},
year  = {2023},
date = {2023-01-01},
journal = {Front Neurosci},
volume = {17},
pages = {1123327},
abstract = {PURPOSE: FINCA disease (Fibrosis, Neurodegeneration and Cerebral Angiomatosis, OMIM 618278) is an infantile-onset neurodevelopmental and multiorgan disease. Since our initial report in 2018, additional patients have been described. FINCA is the first human disease caused by recessive variants in the highly conserved  gene. Our previous studies have shown that Nhlrc2null mouse embryos die during gastrulation, indicating the essential role of the protein in embryonic development. Defect in NHLRC2 leads to cerebral neurodegeneration and severe pulmonary, hepatic and cardiac fibrosis. Despite having a structure suggestive of an enzymatic role and the clinical importance of NHLRC2 in multiple organs, the specific physiological role of the protein is unknown.nnMETHODS: The clinical histories of five novel FINCA patients diagnosed with whole exome sequencing were reviewed. Segregation analysis of the biallelic, potentially pathogenic  variants was performed using Sanger sequencing. Studies on neuropathology and NHLRC2 expression in different brain regions were performed on autopsy samples of three previously described deceased FINCA patients.nnRESULTS: One patient was homozygous for the pathogenic variant c.442G > T, while the other four were compound heterozygous for this variant and two other pathogenic  gene variants. All five patients presented with multiorgan dysfunction with neurodevelopmental delay, recurrent infections and macrocytic anemia as key features. Interstitial lung disease was pronounced in infancy but often stabilized. Autopsy samples revealed widespread, albeit at a lower intensity than the control, NHLRC2 expression in the brain.nnCONCLUSION: This report expands on the characteristic clinical features of FINCA disease. Presentation is typically in infancy, and although patients can live to late adulthood, the key clinical and histopathological features are fibrosis, infection susceptibility/immunodeficiency/intellectual disability, neurodevelopmental disorder/neurodegeneration and chronic anemia/cerebral angiomatosis (hence the acronym FINCA) that enable an early diagnosis confirmed by genetic investigations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36581385,
title = {Editors' Best of 2022},
author = {Douglas K Novins and Robert R Althoff and Melissa A Brotman and Samuele Cortese and Melissa DelBello and Alysa Doyle and Stacy S Drury and Lisa Fortuna and Jean A Frazier and Mary Fristad and Schuyler W Henderson and Elizabeth McCauley and Christel Middeldorp and Wanjikũ F M Njoroge and Cynthia E Rogers and Tonya White},
doi = {10.1016/j.jaac.2022.10.002},
issn = {1527-5418},
year  = {2023},
date = {2023-01-01},
journal = {J Am Acad Child Adolesc Psychiatry},
volume = {62},
number = {1},
pages = {1--7},
abstract = {There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, hammering version after version into shape. Acknowledging these biases, here are the 2022 articles that we think deserve your attention or at least a second read.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36711797,
title = {Base editing as a genetic treatment for spinal muscular atrophy},
author = {Christiano R R Alves and Leillani L Ha and Rebecca Yaworski and Cicera R Lazzarotto and Kathleen A Christie and Aoife Reilly and Ariane Beauvais and Roman M Doll and Demitri de la Cruz and Casey A Maguire and Kathryn J Swoboda and Shengdar Q Tsai and Rashmi Kothary and Benjamin P Kleinstiver},
doi = {10.1101/2023.01.20.524978},
year  = {2023},
date = {2023-01-01},
journal = {bioRxiv},
abstract = {Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by mutations in the  gene. Despite the development of various therapies, outcomes can remain suboptimal in SMA infants and the duration of such therapies are uncertain.  is a paralogous gene that mainly differs from  by a C•G-to-T•A transition in exon 7, resulting in the skipping of exon 7 in most  transcripts and production of only low levels of survival motor neuron (SMN) protein. Genome editing technologies targeted to the  exon 7 mutation could offer a therapeutic strategy to restore SMN protein expression to normal levels irrespective of the patient  mutation. Here, we optimized a base editing approach to precisely edit  , reverting the exon 7 mutation via an A•T-to-G•C base edit. We tested a range of different adenosine base editors (ABEs) and Cas9 enzymes, resulting in up to 99% intended editing in SMA patient-derived fibroblasts with concomitant increases in  exon 7 transcript expression and SMN protein levels. We generated and characterized ABEs fused to high-fidelity Cas9 variants which reduced potential off-target editing. Delivery of these optimized ABEs via dual adeno-associated virus (AAV) vectors resulted in precise  editing  in an SMA mouse model. This base editing approach to correct  should provide a long-lasting genetic treatment for SMA with advantages compared to current nucleic acid, small molecule, or exogenous gene replacement therapies. More broadly, our work highlights the potential of PAMless SpRY base editors to install edits efficiently and safely.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36593295,
title = {Evolution of CRISPR-associated endonucleases as inferred from resurrected proteins},
author = {Borja Alonso-Lerma and Ylenia Jabalera and Sara Samperio and Matias Morin and Almudena Fernandez and Logan T Hille and Rachel A Silverstein and Ane Quesada-Ganuza and Antonio Reifs and Sergio Fernández-Peñalver and Yolanda Benitez and Lucia Soletto and Jose A Gavira and Adrian Diaz and Wim Vranken and Avencia Sanchez-Mejias and Marc Güell and Francisco J M Mojica and Benjamin P Kleinstiver and Miguel A Moreno-Pelayo and Lluis Montoliu and Raul Perez-Jimenez},
doi = {10.1038/s41564-022-01265-y},
issn = {2058-5276},
year  = {2023},
date = {2023-01-01},
journal = {Nat Microbiol},
volume = {8},
number = {1},
pages = {77--90},
abstract = {Clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 is an effector protein that targets invading DNA and plays a major role in the prokaryotic adaptive immune system. Although Streptococcus pyogenes CRISPR-Cas9 has been widely studied and repurposed for applications including genome editing, its origin and evolution are poorly understood. Here, we investigate the evolution of Cas9 from resurrected ancient nucleases (anCas) in extinct firmicutes species that last lived 2.6 billion years before the present. We demonstrate that these ancient forms were much more flexible in their guide RNA and protospacer-adjacent motif requirements compared with modern-day Cas9 enzymes. Furthermore, anCas portrays a gradual palaeoenzymatic adaptation from nickase to double-strand break activity, exhibits high levels of activity with both single-stranded DNA and single-stranded RNA targets and is capable of editing activity in human cells. Prediction and characterization of anCas with a resurrected protein approach uncovers an evolutionary trajectory leading to functionally flexible ancient enzymes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36650173,
title = {BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases},
author = {Saaket Agrawal and Marcus D R Klarqvist and Nathaniel Diamant and Takara L Stanley and Patrick T Ellinor and Nehal N Mehta and Anthony Philippakis and Kenney Ng and Melina Claussnitzer and Steven K Grinspoon and Puneet Batra and Amit V Khera},
doi = {10.1038/s41467-022-35704-5},
issn = {2041-1723},
year  = {2023},
date = {2023-01-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {266},
abstract = {For any given body mass index (BMI), individuals vary substantially in fat distribution, and this variation may have important implications for cardiometabolic risk. Here, we study disease associations with BMI-independent variation in visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) fat depots in 40,032 individuals of the UK Biobank with body MRI. We apply deep learning models based on two-dimensional body MRI projections to enable near-perfect estimation of fat depot volumes (R in heldout dataset = 0.978-0.991 for VAT, ASAT, and GFAT). Next, we derive BMI-adjusted metrics for each fat depot (e.g. VAT adjusted for BMI, VATadjBMI) to quantify local adiposity burden. VATadjBMI is associated with increased risk of type 2 diabetes and coronary artery disease, ASATadjBMI is largely neutral, and GFATadjBMI is associated with reduced risk. These results - describing three metabolically distinct fat depots at scale - clarify the cardiometabolic impact of BMI-independent differences in body fat distribution.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37609073,
title = {Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV},
author = {Madison Sangster and Sanjid Shahriar and Zachary Niziolek and Maria Carla Carisi and Michael Lewandowski and Bogdan Budnik and Yulia Grishchuk},
doi = {10.3389/fnmol.2023.1215425},
issn = {1662-5099},
year  = {2023},
date = {2023-01-01},
journal = {Front Mol Neurosci},
volume = {16},
pages = {1215425},
abstract = {Mucolipidosis IV (MLIV) is an ultra-rare, recessively inherited lysosomal disorder resulting from inactivating mutations in , the gene encoding the lysosomal cation channel TRPML1. The disease primarily affects the central nervous system (CNS) and manifests in the first year with cognitive and motor developmental delay, followed by a gradual decline in neurological function across the second decade of life, blindness, and premature death in third or fourth decades. Brain pathology manifestations in MLIV are consistent with hypomyelinating leukodystrophy with brain iron accumulation. Presently, there are no approved or investigational therapies for MLIV, and pathogenic mechanisms remain largely unknown. The MLIV mouse model,  mice, recapitulates all major manifestations of the human disease. Here, to better understand the pathological mechanisms in the MLIV brain, we performed cell type specific LC-MS/MS proteomics analysis in the MLIV mouse model and reconstituted molecular signatures of the disease in either freshly isolated populations of neurons, astrocytes, oligodendrocytes, and neural stem cells, or whole tissue cortical homogenates from young adult symptomatic  mice. Our analysis confirmed on the molecular level major histopathological hallmarks of MLIV universally present in  tissue and brain cells, such as hypomyelination, lysosomal dysregulation, and impaired metabolism of lipids and polysaccharides. Importantly, pathway analysis in brain cells revealed mitochondria-related alterations in all  brain cells, except oligodendrocytes, that was not possible to resolve in whole tissue. We also report unique proteome signatures and dysregulated pathways for each brain cell population used in this study. These data shed new light on cell-intrinsic mechanisms of MLIV and provide new insights for biomarker discovery and validation to advance translational studies for this disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36653534,
title = {Genetic analyses implicate complex links between adult testosterone levels and health and disease},
author = {Jaakko T Leinonen and Nina Mars and Leevi E Lehtonen and Ari Ahola-Olli and Sanni Ruotsalainen and Terho Lehtimäki and Mika Kähönen and Olli Raitakari and  and Terhi Piltonen and Mark Daly and Tiinamaija Tuomi and Samuli Ripatti and Matti Pirinen and Taru Tukiainen},
doi = {10.1038/s43856-022-00226-0},
issn = {2730-664X},
year  = {2023},
date = {2023-01-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {4},
abstract = {BACKGROUND: Testosterone levels are linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on the role of genetically determined testosterone on complex diseases in both sexes.nnMETHODS: Leveraging genetic and health registry data from the UK Biobank and FinnGen (total N = 625,650), we constructed polygenic scores (PGS) for total testosterone, sex-hormone binding globulin (SHBG) and free testosterone, associating these with 36 endpoints across different disease categories in the FinnGen. These analyses were combined with Mendelian Randomization (MR) and cross-sex PGS analyses to address causality.nnRESULTS: We show testosterone and SHBG levels are intricately tied to metabolic health, but report lack of causality behind most associations, including type 2 diabetes (T2D). Across other disease domains, including 13 behavioral and neurological diseases, we similarly find little evidence for a substantial contribution from normal variation in testosterone levels. We nonetheless find genetically predicted testosterone affects many sex-specific traits, with a pronounced impact on female reproductive health, including causal contribution to PCOS-related traits like hirsutism and post-menopausal bleeding (PMB). We also illustrate how testosterone levels associate with antagonistic effects on stroke risk and reproductive endpoints between the sexes.nnCONCLUSIONS: Overall, these findings provide insight into how genetically determined testosterone correlates with several health parameters in both sexes. Yet the lack of evidence for a causal contribution to most traits beyond sex-specific health underscores the complexity of the mechanisms linking testosterone levels to disease risk and sex differences.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36653479,
title = {Genetic predictors of lifelong medication-use patterns in cardiometabolic diseases},
author = {Tuomo Kiiskinen and Pyry Helkkula and Kristi Krebs and Juha Karjalainen and Elmo Saarentaus and Nina Mars and Arto Lehisto and Wei Zhou and Mattia Cordioli and Sakari Jukarainen and Joel T Rämö and Juha Mehtonen and Kumar Veerapen and Markus Räsänen and Sanni Ruotsalainen and Mutaamba Maasha and  and Teemu Niiranen and Tiinamaija Tuomi and Veikko Salomaa and Mitja Kurki and Matti Pirinen and Aarno Palotie and Mark Daly and Andrea Ganna and Aki S Havulinna and Lili Milani and Samuli Ripatti},
doi = {10.1038/s41591-022-02122-5},
issn = {1546-170X},
year  = {2023},
date = {2023-01-01},
journal = {Nat Med},
volume = {29},
number = {1},
pages = {209--218},
abstract = {Little is known about the genetic determinants of medication use in preventing cardiometabolic diseases. Using the Finnish nationwide drug purchase registry with follow-up since 1995, we performed genome-wide association analyses of longitudinal patterns of medication use in hyperlipidemia, hypertension and type 2 diabetes in up to 193,933 individuals (55% women) in the FinnGen study. In meta-analyses of up to 567,671 individuals combining FinnGen with the Estonian Biobank and the UK Biobank, we discovered 333 independent loci (P < 5 × 10) associated with medication use. Fine-mapping revealed 494 95% credible sets associated with the total number of medication purchases, changes in medication combinations or treatment discontinuation, including 46 credible sets in 40 loci not associated with the underlying treatment targets. The polygenic risk scores (PRS) for cardiometabolic risk factors were strongly associated with the medication-use behavior. A medication-use enhanced multitrait PRS for coronary artery disease matched the performance of a risk factor-based multitrait coronary artery disease PRS in an independent sample (UK Biobank, n = 343,676). In summary, we demonstrate medication-based strategies for identifying cardiometabolic risk loci and provide genome-wide tools for preventing cardiovascular diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36353993,
title = {Genomic Aging, Clonal Hematopoiesis, and Cardiovascular Disease},
author = {Pradeep Natarajan},
doi = {10.1161/ATVBAHA.122.318181},
issn = {1524-4636},
year  = {2023},
date = {2023-01-01},
journal = {Arterioscler Thromb Vasc Biol},
volume = {43},
number = {1},
pages = {3--14},
abstract = {Chronologic age is the dominant risk factor for coronary artery disease but the features of aging promoting coronary artery disease are poorly understood. Advances in human genetics and population-based genetic profiling of blood cells have uncovered the surprising role of age-related subclinical leukemogenic mutations in blood cells, termed "clonal hematopoiesis of indeterminate potential," in coronary artery disease. Such mutations typically occur in , , , and . Murine and human studies prioritize the role of key inflammatory pathways linking clonal hematopoiesis with coronary artery disease. Increasingly larger, longitudinal, multiomics analyses are enabling further dissection into mechanistic insights. These observations expand the genetic architecture of coronary artery disease, now linking hallmark features of hematologic neoplasia with a much more common cardiovascular condition. Implications of these studies include the prospect of novel precision medicine paradigms for coronary artery disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36315649,
title = {Advances and Applications of Polygenic Scores for Coronary Artery Disease},
author = {Aniruddh P Patel and Amit V Khera},
doi = {10.1146/annurev-med-042921-112629},
issn = {1545-326X},
year  = {2023},
date = {2023-01-01},
journal = {Annu Rev Med},
volume = {74},
pages = {141--154},
abstract = {Polygenic scores quantify inherited risk by integrating information from many common sites of DNA variation into a single number. Rapid increases in the scale of genetic association studies and new statistical algorithms have enabled development of polygenic scores that meaningfully measure-as early as birth-risk of coronary artery disease. These newer-generation polygenic scores identify up to 8% of the population with triple the normal risk based on genetic variation alone, and these individuals cannot be identified on the basis of family history or clinical risk factors alone. For those identified with increased genetic risk, evidence supports risk reduction with at least two interventions, adherence to a healthy lifestyle and cholesterol-lowering therapies, that can substantially reduce risk. Alongside considerable enthusiasm for the potential of polygenic risk estimation to enable a new era of preventive clinical medicine is recognition of a need for ongoing research into how best to ensure equitable performance across diverse ancestries, how and in whom to assess the scores in clinical practice, as well as randomized trials to confirm clinical utility.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36705922,
title = {Peer Review in a General Medical Research Journal Before and During the COVID-19 Pandemic},
author = {Roy H Perlis and Jacob Kendall-Taylor and Kamber Hart and Ishani Ganguli and Jesse A Berlin and Steven M Bradley and Sebastien Haneuse and Sharon K Inouye and Elizabeth A Jacobs and Arden Morris and Olugbenga Ogedegbe and Eli Perencevich and Lawrence N Shulman and N Seth Trueger and Stephan D Fihn and Frederick P Rivara and Annette Flanagin},
doi = {10.1001/jamanetworkopen.2022.53296},
issn = {2574-3805},
year  = {2023},
date = {2023-01-01},
journal = {JAMA Netw Open},
volume = {6},
number = {1},
pages = {e2253296},
abstract = {IMPORTANCE: Although peer review is an important component of publication for new research, the viability of this process has been questioned, particularly with the added stressors of the COVID-19 pandemic.nnOBJECTIVE: To characterize rates of peer reviewer acceptance of invitations to review manuscripts, reviewer turnaround times, and editor-assessed quality of reviews before and after the start of the COVID-19 pandemic at a large, open-access general medical journal.nnDESIGN, SETTING, AND PARTICIPANTS: This retrospective, pre-post cohort study examined all research manuscripts submitted to JAMA Network Open between January 1, 2019, and June 29, 2021, either directly or via transfer from other JAMA Network journals, for which at least 1 peer review of manuscript content was solicited. Measures were compared between the period before the World Health Organization declaration of a COVID-19 pandemic on March 11, 2020 (14.3 months), and the period during the pandemic (15.6 months) among all reviewed manuscripts and between pandemic-period manuscripts that did or did not address COVID-19.nnMAIN OUTCOMES AND MEASURES: For each reviewed manuscript, the number of invitations sent to reviewers, proportions of reviewers accepting invitations, time in days to return reviews, and editor-assessed quality ratings of reviews were determined.nnRESULTS: In total, the journal sought review for 5013 manuscripts, including 4295 Original Investigations (85.7%) and 718 Research Letters (14.3%); 1860 manuscripts were submitted during the prepandemic period and 3153 during the pandemic period. Comparing the prepandemic with the pandemic period, the mean (SD) number of reviews rated as high quality (very good or excellent) per manuscript increased slightly from 1.3 (0.7) to 1.5 (0.7) (P < .001), and the mean (SD) time for reviewers to return reviews was modestly shorter (from 15.8 [7.6] days to 14.4 [7.0] days; P < .001), a difference that persisted in linear regression models accounting for manuscript type, study design, and whether the manuscript addressed COVID-19.nnCONCLUSIONS AND RELEVANCE: In this cohort study, the speed and editor-reported quality of peer reviews in an open-access general medical journal improved modestly during the initial year of the pandemic. Additional study will be necessary to understand how the pandemic has affected reviewer burden and fatigue.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36777179,
title = {Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts},
author = {Ying Wang and Shinichi Namba and Esteban Lopera and Sini Kerminen and Kristin Tsuo and Kristi Läll and Masahiro Kanai and Wei Zhou and Kuan-Han Wu and Marie-Julie Favé and Laxmi Bhatta and Philip Awadalla and Ben Brumpton and Patrick Deelen and Kristian Hveem and Valeria Lo Faro and Reedik Mägi and Yoshinori Murakami and Serena Sanna and Jordan W Smoller and Jasmina Uzunovic and Brooke N Wolford and  and Cristen Willer and Eric R Gamazon and Nancy J Cox and Ida Surakka and Yukinori Okada and Alicia R Martin and Jibril Hirbo},
doi = {10.1016/j.xgen.2022.100241},
issn = {2666-979X},
year  = {2023},
date = {2023-01-01},
journal = {Cell Genom},
volume = {3},
number = {1},
pages = {100241},
abstract = {Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36615904,
title = {Effects of Initial Combinations of Gemigliptin Plus Metformin Compared with Glimepiride Plus Metformin on Gut Microbiota and Glucose Regulation in Obese Patients with Type 2 Diabetes: The INTESTINE Study},
author = {Soo Lim and Minji Sohn and Jose C Florez and Michael A Nauck and Jiyoung Ahn},
doi = {10.3390/nu15010248},
issn = {2072-6643},
year  = {2023},
date = {2023-01-01},
journal = {Nutrients},
volume = {15},
number = {1},
abstract = {The efficacy and safety of medications can be affected by alterations in gut microbiota in human beings. Among antidiabetic medications, incretin-based therapy such as dipeptidyl peptidase 4 inhibitors might affect gut microbiomes, which are related to glucose metabolism. This was a randomized, controlled, active-competitor study that aimed to compare the effects of combinations of gemigliptin−metformin vs. glimepiride−metformin as initial therapies on gut microbiota and glucose homeostasis in drug-naïve patients with type 2 diabetes. Seventy drug-naïve patients with type 2 diabetes (mean age, 52.2 years) with a glycated hemoglobin (HbA1c) level ≥7.5% were assigned to either gemigliptin−metformin or glimepiride−metformin combination therapies for 24 weeks. Changes in gut microbiota, biomarkers linked to glucose regulation, body composition, and amino acid blood levels were investigated. Although both treatments decreased the HbA1c levels significantly, the gemigliptin−metformin group achieved HbA1c ≤ 7.0% without hypoglycemia or weight gain more effectively than did the glimepiride−metformin group (59% vs. 24%; p < 0.05). At the phylum level, the Firmicutes/Bacteroidetes ratio tended to decrease after gemigliptin−metformin therapy (p = 0.065), with a notable depletion of taxa belonging to Firmicutes, including Lactobacillus, Ruminococcus torques, and Streptococcus (all p < 0.05). However, regardless of the treatment modality, a distinct difference in the overall gut microbiome composition was noted between patients who reached the HbA1c target goal and those who did not (p < 0.001). Treatment with gemigliptin−metformin resulted in a higher achievement of the glycemic target without hypoglycemia or weight gain, better than with glimepiride−metformin; these improvements might be related to beneficial changes in gut microbiota.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36444719,
title = {Association of Depression Onset and Treatment With Blood Pressure Control After Intracerebral Hemorrhage},
author = {Sophia Keins and Jessica R Abramson and Akashleena Mallick and Juan Pablo Castello and Axana Rodriguez-Torres and Dominique Popescu and Danielle Hoffman and Christina Kourkoulis and M Edip Gurol and Steven M Greenberg and Christopher D Anderson and Anand Viswanathan and Jonathan Rosand and Alessandro Biffi},
doi = {10.1161/STROKEAHA.122.040331},
issn = {1524-4628},
year  = {2023},
date = {2023-01-01},
journal = {Stroke},
volume = {54},
number = {1},
pages = {105--112},
abstract = {BACKGROUND: Blood pressure (BP) control represents a crucial intervention to improve long-term outcomes following spontaneous intracerebral hemorrhage (ICH). However, fewer than half of ICH survivors achieve target treatment goals. ICH survivors are also at very high risk for poststroke depression, which may contribute to inadequate BP control. We, therefore, sought to determine whether depressive symptoms after ICH are associated with inadequate BP control. We also investigated whether associations between depression after ICH and BP measurements were mediated by treatment with selective serotonin reuptake inhibitors or norepinephrine-serotonin reuptake inhibitors antidepressants.nnMETHODS: We leveraged data from a single-center longitudinal study of ICH conducted at Massachusetts General Hospital (Boston, MA) between 2006 and 2018. We collected data from semiautomated review of electronic health records, baseline and follow-up interviews, and computed tomography imaging. Information on BP measurements, depression diagnoses, antidepressants medication use, and medical visits were collected longitudinally and analyzed using mixed effects models. Primary outcomes included systolic and diastolic BP measurements during long-term follow-up after ICH.nnRESULTS: We included 1243 consecutive ICH patients without pre-stroke depression history. Of these, 721 (58%) were diagnosed with incident depression over a median follow-up time of 52.8 months (interquartile range, 42.1-60.5). Depression onset was associated with subsequent increase in systolic (+8.3 mm Hg, SE, 2.4 mm Hg, =0.012) and diastolic (+4.4 mm Hg, SE, 1.2 mm Hg) BP measurements. Resolution of depressive symptoms was associated with subsequent decrease in systolic (-5.9 mm Hg, SE, 1.4 mm Hg, =0.031) and diastolic (-3.4 mm Hg, SE, 1.1 mm Hg, =0.041) BP measurements. We also found associations between higher systolic BP measurements and use of selective serotonin reuptake inhibitor and noradrenaline-serotonin reuptake inhibitor antidepressants, independent of whether depression symptoms were active or not (all <0.05).nnCONCLUSIONS: ICH survivors displayed increasing BP values after receiving a diagnosis of depression, followed by decreasing values among those experiencing resolution of depressive symptoms. Use of selective serotonin reuptake inhibitor and noradrenaline-serotonin reuptake inhibitor antidepressants was independently associated with higher systolic BP measurements. Clinicians ought to closely monitor BP for ICH survivors being treated for depression, especially using selective serotonin reuptake inhibitor and noradrenaline-serotonin reuptake inhibitor. Future studies will also be required to investigate the mechanisms underlying these associations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36541006,
title = {Accessing clinical-grade genomic classification data through the ClinGen Data Platform},
author = {Karen P Dalton and Heidi L Rehm and Matt W Wright and Mark E Mandell and Kilannin Krysiak and Lawrence Babb and Kevin Riehle and Tristan Nelson and Alex H Wagner},
issn = {2335-6936},
year  = {2023},
date = {2023-01-01},
journal = {Pac Symp Biocomput},
volume = {28},
pages = {531--535},
abstract = {The Clinical Genome Resource (ClinGen) serves as an authoritative resource on the clinical relevance of genes and variants. In order to support our curation activities and to disseminate our findings to the community, we have developed a Data Platform of informatics resources backed by standardized data models. In this workshop we demonstrate our publicly available resources including curation interfaces, (Variant Curation Interface, CIViC), supporting infrastructure (Allele Registry, Genegraph), and data models (SEPIO, GA4GH VRS, VA).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37779905,
title = {Metabolite profiles and DNA methylation in metabolic syndrome: a two-sample, bidirectional Mendelian randomization},
author = {Alana C Jones and Zsuzsanna Ament and Amit Patki and Ninad S Chaudhary and Vinodh Srinivasasainagendra and Naruchorn Kijpaisalratana and Devin M Absher and Hemant K Tiwari and Donna K Arnett and W Taylor Kimberly and Marguerite R Irvin},
doi = {10.3389/fgene.2023.1184661},
issn = {1664-8021},
year  = {2023},
date = {2023-01-01},
journal = {Front Genet},
volume = {14},
pages = {1184661},
abstract = { Metabolic syndrome (MetS) increases the risk of cardiovascular disease and death. Previous '-omics' studies have identified dysregulated serum metabolites and aberrant DNA methylation in the setting of MetS. However, the relationship between the metabolome and epigenome have not been elucidated. In this study, we identified serum metabolites associated with MetS and DNA methylation, and we conducted bidirectional Mendelian randomization (MR) to assess causal relationships between metabolites and methylation.  We leveraged metabolomic and genomic data from a national United States cohort of older adults (REGARDS), as well as metabolomic, epigenomic, and genomic data from a family-based study of hypertension (HyperGEN). We conducted metabolite profiling for MetS in REGARDS using weighted logistic regression models and validated them in HyperGEN. Validated metabolites were selected for methylation studies which fit linear mixed models between metabolites and six CpG sites previously linked to MetS. Statistically significant metabolite-CpG pairs were selected for two-sample, bidirectional MR.  Forward MR indicated that glucose and serine metabolites were causal on CpG methylation near  [B(SE): -0.003 (0.002),  = 0.028 and B(SE): 0.029 (0.011),  = 0.030, respectively] and that serine metabolites were causal on  [B(SE): -0.008(0.003),  = 0.006] and  [B(SE): -0.009(0.004),  = 0.018] methylation which suggested a protective effect of serine. Reverse MR showed a bidirectional relationship between cg06500161 () and serine [B(SE): -1.534 (0.668),  = 0.023].  The metabolome may contribute to the relationship between MetS and epigenetic modifications.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36548704,
title = {"The Times They Are A-Changin'" at Diabetes Care},
author = {Steven E Kahn and Cheryl A M Anderson and John B Buse and Elizabeth Selvin and Sonia Y Angell and Vanita R Aroda and Jessica R Castle and Alice Y Y Cheng and Thomas Danne and Justin B Echouffo-Tcheugui and Jose C Florez and Meghana D Gadgil and Amalia Gastaldelli and Jennifer B Green and Ania M Jastreboff and Alka M Kanaya and Namratha R Kandula and Csaba P Kovesdy and Neda Laiteerapong and Kristen J Nadeau and Rodica Pop-Busui and Camille E Powe and Casey M Rebholz and Michael R Rickels and Naveed Sattar and Jonathan E Shaw and Emily K Sims and Kristina M Utzschneider and Adrian Vella and Cuilin Zhang},
doi = {10.2337/dci22-0045},
issn = {1935-5548},
year  = {2023},
date = {2023-01-01},
journal = {Diabetes Care},
volume = {46},
number = {1},
pages = {3--5},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36713248,
title = {Beyond the exome: what's next in diagnostic testing for Mendelian conditions},
author = {Monica H Wojcik and Chloe M Reuter and Shruti Marwaha and Medhat Mahmoud and Michael H Duyzend and Hayk Barseghyan and Bo Yuan and Philip M Boone and Emily E Groopman and Emmanuèle C Délot and Deepti Jain and Alba Sanchis-Juan and  and Lea M Starita and Michael Talkowski and Stephen B Montgomery and Michael J Bamshad and Jessica X Chong and Matthew T Wheeler and Seth I Berger and Anne O'Donnell-Luria and Fritz J Sedlazeck and Danny E Miller},
issn = {2331-8422},
year  = {2023},
date = {2023-01-01},
journal = {ArXiv},
abstract = {Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order and emerging technologies, such as optical genome mapping and long-read DNA or RNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to a consortium such as GREGoR, which is focused on elucidating the underlying cause of rare unsolved genetic disorders.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36755575,
title = {Ancestry: How researchers use it and what they mean by it},
author = {Bege Dauda and Santiago J Molina and Danielle S Allen and Agustin Fuentes and Nayanika Ghosh and Madelyn Mauro and Benjamin M Neale and Aaron Panofsky and Mashaal Sohail and Sarah R Zhang and Anna C F Lewis},
doi = {10.3389/fgene.2023.1044555},
issn = {1664-8021},
year  = {2023},
date = {2023-01-01},
journal = {Front Genet},
volume = {14},
pages = {1044555},
abstract = { Ancestry is often viewed as a more objective and less objectionable population descriptor than race or ethnicity. Perhaps reflecting this, usage of the term "ancestry" is rapidly growing in genetics research, with ancestry groups referenced in many situations. The appropriate usage of population descriptors in genetics research is an ongoing source of debate. Sound normative guidance should rest on an empirical understanding of current usage; in the case of ancestry, questions about how researchers use the concept, and what they mean by it, remain unanswered.  Systematic literature analysis of 205 articles at least tangentially related to human health from diverse disciplines that use the concept of ancestry, and semi-structured interviews with 44 lead authors of some of those articles.  Ancestry is relied on to structure research questions and key methodological approaches. Yet researchers struggle to define it, and/or offer diverse definitions. For some ancestry is a genetic concept, but for many-including geneticists-ancestry is only tangentially related to genetics. For some interviewees, ancestry is explicitly equated to ethnicity; for others it is explicitly distanced from it. Ancestry is operationalized using multiple data types (including genetic variation and self-reported identities), though for a large fraction of articles (26%) it is impossible to tell which data types were used. Across the literature and interviews there is no consistent understanding of how ancestry relates to genetic concepts (including genetic ancestry and population structure), nor how these genetic concepts relate to each other. Beyond this conceptual confusion, practices related to summarizing patterns of genetic variation often rest on uninterrogated conventions. Continental labels are by far the most common type of label applied to ancestry groups. We observed many instances of slippage between reference to ancestry groups and racial groups.  Ancestry is in practice a highly ambiguous concept, and far from an objective counterpart to race or ethnicity. It is not uniquely a "biological" construct, and it does not represent a "safe haven" for researchers seeking to avoid evoking race or ethnicity in their work. Distinguishing genetic ancestry from ancestry more broadly will be a necessary part of providing conceptual clarity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36403757,
title = {COMMUTE: Communication-efficient transfer learning for multi-site risk prediction},
author = {Tian Gu and Phil H Lee and Rui Duan},
doi = {10.1016/j.jbi.2022.104243},
issn = {1532-0480},
year  = {2023},
date = {2023-01-01},
journal = {J Biomed Inform},
volume = {137},
pages = {104243},
abstract = {OBJECTIVES: We propose a communication-efficient transfer learning approach (COMMUTE) that effectively incorporates multi-site healthcare data for training a risk prediction model in a target population of interest, accounting for challenges including population heterogeneity and data sharing constraints across sites.nnMETHODS: We first train population-specific source models locally within each site. Using data from a given target population, COMMUTE learns a calibration term for each source model, which adjusts for potential data heterogeneity through flexible distance-based regularizations. In a centralized setting where multi-site data can be directly pooled, all data are combined to train the target model after calibration. When individual-level data are not shareable in some sites, COMMUTE requests only the locally trained models from these sites, with which, COMMUTE generates heterogeneity-adjusted synthetic data for training the target model. We evaluate COMMUTE via extensive simulation studies and an application to multi-site data from the electronic Medical Records and Genomics (eMERGE) Network to predict extreme obesity.nnRESULTS: Simulation studies show that COMMUTE outperforms methods without adjusting for population heterogeneity and methods trained in a single population over a broad spectrum of settings. Using eMERGE data, COMMUTE achieves an area under the receiver operating characteristic curve (AUC) around 0.80, which outperforms other benchmark methods with AUC ranging from 0.51 to 0.70.nnCONCLUSION: COMMUTE improves the risk prediction in a target population with limited samples and safeguards against negative transfer when some source populations are highly different from the target. In a federated setting, it is highly communication efficient as it only requires each site to share model parameter estimates once, and no iterative communication or higher-order terms are needed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37360335,
title = {Disparities in brain health comorbidity management in intracerebral hemorrhage},
author = {Ernst Mayerhofer and Natalie O Zaba and Livia Parodi and Alena S Ganbold and Alessandro Biffi and Jonathan Rosand and Nirupama Yechoor and Christopher D Anderson},
doi = {10.3389/fneur.2023.1194810},
issn = {1664-2295},
year  = {2023},
date = {2023-01-01},
journal = {Front Neurol},
volume = {14},
pages = {1194810},
abstract = {BACKGROUND: Intracerebral hemorrhage (ICH) disproportionally affects underserved populations, and coincides with risk factors for cardiovascular events and cognitive decline after ICH. We investigated associations between social determinants of health and management of blood pressure (BP), hyperlipidemia, diabetes, obstructive sleep apnea (OSA), and hearing impairment before and after ICH hospitalization.nnMETHODS: Survivors of the Massachusetts General Hospital longitudinal ICH study between 2016 and 2019 who received healthcare at least 6 months after ICH were analyzed. Measurements of BP, LDL and HbA1c and their management in the year surrounding ICH and referrals for sleep studies and audiology up to 6 months after ICH were gathered from electronic health records. The US-wide area deprivation index (ADI) was used as proxy for social determinants of health.nnRESULTS: The study included 234 patients (mean 71 years, 42% female). BP measurements were performed in 109 (47%) before ICH, LDL measurements were performed in 165 (71%), and HbA1c measurements in 154 (66%) patients before or after ICH. 27/59 (46%) with off-target LDL and 3/12 (25%) with off-target HbA1c were managed appropriately. Of those without history of OSA or hearing impairment before ICH, 47/207 (23%) were referred for sleep studies and 16/212 (8%) to audiology. Higher ADI was associated with lower odds of BP, LDL, and HbA1c measurement prior to ICH [OR 0.94 (0.90-0.99), 0.96 (0.93-0.99), and 0.96 (0.93-0.99), respectively, per decile] but not with management during or after hospitalization.nnCONCLUSION: Social determinants of health are associated with pre-ICH management of cerebrovascular risk factors. More than 25% of patients were not assessed for hyperlipidemia and diabetes in the year surrounding ICH hospitalization, and less than half of those with off-target values received treatment intensification. Few patients were evaluated for OSA and hearing impairment, both common among ICH survivors. Future trials should evaluate whether using the ICH hospitalization to systematically address co-morbidities can improve long-term outcomes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36540993,
title = {Development and application of a computable genotype model in the GA4GH Variation Representation Specification},
author = {Wesley Goar and Lawrence Babb and Srikar Chamala and Melissa Cline and Robert R Freimuth and Reece K Hart and Kori Kuzma and Jennifer Lee and Tristan Nelson and Andreas Prlić and Kevin Riehle and Anastasia Smith and Kathryn Stahl and Andrew D Yates and Heidi L Rehm and Alex H Wagner},
issn = {2335-6936},
year  = {2023},
date = {2023-01-01},
journal = {Pac Symp Biocomput},
volume = {28},
pages = {383--394},
abstract = {As the diversity of genomic variation data increases with our growing understanding of the role of variation in health and disease, it is critical to develop standards for precise inter-system exchange of these data for research and clinical applications. The Global Alliance for Genomics and Health (GA4GH) Variation Representation Specification (VRS) meets this need through a technical terminology and information model for disambiguating and concisely representing variation concepts. Here we discuss the recent Genotype model in VRS, which may be used to represent the allelic composition of a genetic locus. We demonstrate the use of the Genotype model and the constituent Haplotype model for the precise and interoperable representation of pharmacogenomic diplotypes, HGVS variants, and VCF records using VRS and discuss how this can be leveraged to enable interoperable exchange and search operations between assayed variation and genomic knowledgebases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid35908190,
title = {Huntingtin turnover: modulation of huntingtin degradation by cAMP-dependent protein kinase A (PKA) phosphorylation of C-HEAT domain Ser2550},
author = {Yejin Lee and Hyeongju Kim and Douglas Barker and Ravi Vijayvargia and Ranjit Singh Atwal and Harrison Specht and Hasmik Keshishian and Steven A Carr and Ramee Lee and Seung Kwak and Kyung-Gi Hyun and Jacob Loupe and Marcy E MacDonald and Ji-Joon Song and Ihn Sik Seong},
doi = {10.1093/hmg/ddac165},
issn = {1460-2083},
year  = {2023},
date = {2023-01-01},
journal = {Hum Mol Genet},
volume = {32},
number = {1},
pages = {30--45},
abstract = {Huntington's disease (HD) is a neurodegenerative disorder caused by an inherited unstable HTT CAG repeat that expands further, thereby eliciting a disease process that may be initiated by polyglutamine-expanded huntingtin or a short polyglutamine-product. Phosphorylation of selected candidate residues is reported to mediate polyglutamine-fragment degradation and toxicity. Here to support the discovery of phosphosites involved in the life-cycle of (full-length) huntingtin, we employed mass spectrometry-based phosphoproteomics to systematically identify sites in purified huntingtin and in the endogenous protein by proteomic and phosphoproteomic analyses of members of an HD neuronal progenitor cell panel. Our results bring total huntingtin phosphosites to 95, with more located in the N-HEAT domain relative to numbers in the Bridge and C-HEAT domains. Moreover, phosphorylation of C-HEAT Ser2550 by cAMP-dependent protein kinase (PKA), the top hit in kinase activity screens, was found to hasten huntingtin degradation, such that levels of the catalytic subunit (PRKACA) were inversely related to huntingtin levels. Taken together, these findings highlight categories of phosphosites that merit further study and provide a phosphosite kinase pair (pSer2550-PKA) with which to investigate the biological processes that regulate huntingtin degradation and thereby influence the steady state levels of huntingtin in HD cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36350676,
title = {FAVOR: functional annotation of variants online resource and annotator for variation across the human genome},
author = {Hufeng Zhou and Theodore Arapoglou and Xihao Li and Zilin Li and Xiuwen Zheng and Jill Moore and Abhijith Asok and Sushant Kumar and Elizabeth E Blue and Steven Buyske and Nancy Cox and Adam Felsenfeld and Mark Gerstein and Eimear Kenny and Bingshan Li and Tara Matise and Anthony Philippakis and Heidi L Rehm and Heidi J Sofia and Grace Snyder and  and Zhiping Weng and Benjamin Neale and Shamil R Sunyaev and Xihong Lin},
doi = {10.1093/nar/gkac966},
issn = {1362-4962},
year  = {2023},
date = {2023-01-01},
journal = {Nucleic Acids Res},
volume = {51},
number = {D1},
pages = {D1300--D1311},
abstract = {Large biobank-scale whole genome sequencing (WGS) studies are rapidly identifying a multitude of coding and non-coding variants. They provide an unprecedented resource for illuminating the genetic basis of human diseases. Variant functional annotations play a critical role in WGS analysis, result interpretation, and prioritization of disease- or trait-associated causal variants. Existing functional annotation databases have limited scope to perform online queries and functionally annotate the genotype data of large biobank-scale WGS studies. We develop the Functional Annotation of Variants Online Resources (FAVOR) to meet these pressing needs. FAVOR provides a comprehensive multi-faceted variant functional annotation online portal that summarizes and visualizes findings of all possible nine billion single nucleotide variants (SNVs) across the genome. It allows for rapid variant-, gene- and region-level queries of variant functional annotations. FAVOR integrates variant functional information from multiple sources to describe the functional characteristics of variants and facilitates prioritizing plausible causal variants influencing human phenotypes. Furthermore, we provide a scalable annotation tool, FAVORannotator, to functionally annotate large-scale WGS studies and efficiently store the genotype and their variant functional annotation data in a single file using the annotated Genomic Data Structure (aGDS) format, making downstream analysis more convenient. FAVOR and FAVORannotator are available at https://favor.genohub.org.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36795700,
title = {Improving risk prediction for target subpopulations: Predicting suicidal behaviors among multiple sclerosis patients},
author = {Yuval Barak-Corren and Victor M Castro and Solomon Javitt and Matthew K Nock and Jordan W Smoller and Ben Y Reis},
doi = {10.1371/journal.pone.0277483},
issn = {1932-6203},
year  = {2023},
date = {2023-01-01},
journal = {PLoS One},
volume = {18},
number = {2},
pages = {e0277483},
abstract = {Several recent studies have applied machine learning techniques to develop risk algorithms that predict subsequent suicidal behavior based on electronic health record data. In this study we used a retrospective cohort study design to test whether developing more tailored predictive models-within specific subpopulations of patients-would improve predictive accuracy. A retrospective cohort of 15,117 patients diagnosed with multiple sclerosis (MS), a diagnosis associated with increased risk of suicidal behavior, was used. The cohort was randomly divided into equal sized training and validation sets. Overall, suicidal behavior was identified among 191 (1.3%) of the patients with MS. A Naïve Bayes Classifier model was trained on the training set to predict future suicidal behavior. With 90% specificity, the model detected 37% of subjects who later demonstrated suicidal behavior, on average 4.6 years before the first suicide attempt. The performance of a model trained only on MS patients was better at predicting suicide in MS patients than that a model trained on a general patient sample of a similar size (AUC of 0.77 vs. 0.66). Unique risk factors for suicidal behavior among patients with MS included pain-related codes, gastroenteritis and colitis, and history of smoking. Future studies are needed to further test the value of developing population-specific risk models.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37195925,
title = {AI-Driven sleep staging from actigraphy and heart rate},
author = {Tzu-An Song and Samadrita Roy Chowdhury and Masoud Malekzadeh and Stephanie Harrison and Terri Blackwell Hoge and Susan Redline and Katie L Stone and Richa Saxena and Shaun M Purcell and Joyita Dutta},
doi = {10.1371/journal.pone.0285703},
issn = {1932-6203},
year  = {2023},
date = {2023-01-01},
journal = {PLoS One},
volume = {18},
number = {5},
pages = {e0285703},
abstract = {Sleep is an important indicator of a person's health, and its accurate and cost-effective quantification is of great value in healthcare. The gold standard for sleep assessment and the clinical diagnosis of sleep disorders is polysomnography (PSG). However, PSG requires an overnight clinic visit and trained technicians to score the obtained multimodality data. Wrist-worn consumer devices, such as smartwatches, are a promising alternative to PSG because of their small form factor, continuous monitoring capability, and popularity. Unlike PSG, however, wearables-derived data are noisier and far less information-rich because of the fewer number of modalities and less accurate measurements due to their small form factor. Given these challenges, most consumer devices perform two-stage (i.e., sleep-wake) classification, which is inadequate for deep insights into a person's sleep health. The challenging multi-class (three, four, or five-class) staging of sleep using data from wrist-worn wearables remains unresolved. The difference in the data quality between consumer-grade wearables and lab-grade clinical equipment is the motivation behind this study. In this paper, we present an artificial intelligence (AI) technique termed sequence-to-sequence LSTM for automated mobile sleep staging (SLAMSS), which can perform three-class (wake, NREM, REM) and four-class (wake, light, deep, REM) sleep classification from activity (i.e., wrist-accelerometry-derived locomotion) and two coarse heart rate measures-both of which can be reliably obtained from a consumer-grade wrist-wearable device. Our method relies on raw time-series datasets and obviates the need for manual feature selection. We validated our model using actigraphy and coarse heart rate data from two independent study populations: the Multi-Ethnic Study of Atherosclerosis (MESA; N = 808) cohort and the Osteoporotic Fractures in Men (MrOS; N = 817) cohort. SLAMSS achieves an overall accuracy of 79%, weighted F1 score of 0.80, 77% sensitivity, and 89% specificity for three-class sleep staging and an overall accuracy of 70-72%, weighted F1 score of 0.72-0.73, 64-66% sensitivity, and 89-90% specificity for four-class sleep staging in the MESA cohort. It yielded an overall accuracy of 77%, weighted F1 score of 0.77, 74% sensitivity, and 88% specificity for three-class sleep staging and an overall accuracy of 68-69%, weighted F1 score of 0.68-0.69, 60-63% sensitivity, and 88-89% specificity for four-class sleep staging in the MrOS cohort. These results were achieved with feature-poor inputs with a low temporal resolution. In addition, we extended our three-class staging model to an unrelated Apple Watch dataset. Importantly, SLAMSS predicts the duration of each sleep stage with high accuracy. This is especially significant for four-class sleep staging, where deep sleep is severely underrepresented. We show that, by appropriately choosing the loss function to address the inherent class imbalance, our method can accurately estimate deep sleep time (SLAMSS/MESA: 0.61±0.69 hours, PSG/MESA ground truth: 0.60±0.60 hours; SLAMSS/MrOS: 0.53±0.66 hours, PSG/MrOS ground truth: 0.55±0.57 hours;). Deep sleep quality and quantity are vital metrics and early indicators for a number of diseases. Our method, which enables accurate deep sleep estimation from wearables-derived data, is therefore promising for a variety of clinical applications requiring long-term deep sleep monitoring.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36908397,
title = {LAVAA: a lightweight association viewer across ailments},
author = {Eric B Fauman and Stella Keppo and Nicola Cerioli and Rupesh Vyas and Mitja Kurki and Mark Daly and Mary Pat Reeve},
doi = {10.1093/bioadv/vbad018},
issn = {2635-0041},
year  = {2023},
date = {2023-01-01},
journal = {Bioinform Adv},
volume = {3},
number = {1},
pages = {vbad018},
abstract = {MOTIVATION: Biobank scale genetic associations results over thousands of traits can be difficult to visualize and navigate.nnRESULTS: We have created LAVAA, a visualization web-application to generate genetic volcano plots for simultaneously considering the -value, effect size, case counts, trait class and fine-mapping posterior probability at a single-nucleotide polymorphism (SNP) across a range of traits from a large set of genome-wide association study. We find that user interaction with association results in LAVAA can enrich and enhance the biological interpretation of individual loci.nnAVAILABILITY AND IMPLEMENTATION: LAVAA is available as a stand-alone web service (https://geneviz.aalto.fi/LAVAA/) and will be available in future releases of the finngen.fi website starting with release 10 in late 2023.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36653477,
title = {Genome-wide association study of varicose veins identifies a protective missense variant in GJD3 enriched in the Finnish population},
author = {Pyry Helkkula and Shabbeer Hassan and Elmo Saarentaus and Emilia Vartiainen and Sanni Ruotsalainen and Jaakko T Leinonen and  and Aarno Palotie and Juha Karjalainen and Mitja Kurki and Samuli Ripatti and Taru Tukiainen},
doi = {10.1038/s42003-022-04285-w},
issn = {2399-3642},
year  = {2023},
date = {2023-01-01},
journal = {Commun Biol},
volume = {6},
number = {1},
pages = {71},
abstract = {Varicose veins is the most common manifestation of chronic venous disease that displays female-biased incidence. To identify protein-inactivating variants that could guide identification of drug target genes for varicose veins and genetic evidence for the disease prevalence difference between the sexes, we conducted a genome-wide association study of varicose veins in Finns using the FinnGen dataset with 17,027 cases and 190,028 controls. We identified 50 associated genetic loci (P < 5.0 × 10) of which 29 were novel including one near ERG with female-specificity (rs2836405-G, OR[95% CI] = 1.09[1.05-1.13], P = 3.1 × 10). These also include two X-chromosomal (ARHGAP6 and SRPX) and two autosomal novel loci (TGFB2 and GJD3) with protein-coding lead variants enriched above 56-fold in Finns over non-Finnish non-Estonian Europeans. A low-frequency missense variant in GJD3 (p.Pro59Thr) is exclusively associated with a lower risk for varicose veins (OR = 0.62 [0.55-0.70], P = 1.0 × 10) in a phenome-wide scan of the FinnGen data. The absence of observed pleiotropy and its membership of the connexin gene family underlines GJD3 as a potential connexin-modulating therapeutic strategy for varicose veins. Our results provide insights into varicose veins etiopathology and highlight the power of isolated populations, including Finns, to discover genetic variants that inform therapeutic development.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36778285,
title = {Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection},
author = {Aoxing Liu and Giulio Genovese and Yajie Zhao and Matti Pirinen and Maryam M Zekavat and Katherine Kentistou and Zhiyu Yang and Kai Yu and Caitlyn Vlasschaert and Xiaoxi Liu and Derek W Brown and Georgi Hudjashov and Bryan Gorman and Joe Dennis and Weiyin Zhou and Yukihide Momozawa and Saiju Pyarajan and Vlad Tuzov and Fanny-Dhelia Pajuste and Mervi Aavikko and Timo P Sipilä and Awaisa Ghazal and Wen-Yi Huang and Neal Freedman and Lei Song and Eugene J Gardner and  and  and  and Vijay G Sankaran and Aarno Palotie and Hanna M Ollila and Taru Tukiainen and Stephen J Chanock and Reedik Mägi and Pradeep Natarajan and Mark J Daly and Alexander Bick and Steven A McCarroll and Chikashi Terao and Po-Ru Loh and Andrea Ganna and John R B Perry and Mitchell J Machiela},
doi = {10.1101/2023.01.28.23285140},
year  = {2023},
date = {2023-01-01},
journal = {medRxiv},
abstract = {Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in >900,000 women across eight biobanks, identifying 10% of women with detectable X loss in approximately 2% of their leukocytes. Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Genetic analyses identified 49 common variants influencing mLOX, implicating genes with established roles in chromosomal missegregation, cancer predisposition, and autoimmune diseases. Complementary exome-sequence analyses identified rare missense variants in  which confer a two-fold increased risk of mLOX. A small fraction of these associations were shared with mosaic Y chromosome loss in men, suggesting different biological processes drive the formation and clonal expansion of sex chromosome missegregation events. Allelic shift analyses identified alleles on the X chromosome which are preferentially retained, demonstrating that variation at many loci across the X chromosome is under cellular selection. A novel polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Collectively our results support a model where germline variants predispose women to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of subsequent clonal expansion.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36651666,
title = {GWAS quality score for evaluating associated regions in GWAS analyses},
author = {Swapnil Awasthi and Chia-Yen Chen and Max Lam and Hailiang Huang and Stephan Ripke and C Anthony Altar},
doi = {10.1093/bioinformatics/btad004},
issn = {1367-4811},
year  = {2023},
date = {2023-01-01},
journal = {Bioinformatics},
volume = {39},
number = {1},
abstract = {MOTIVATION: The number of significantly associated regions reported in genome-wide association studies (GWAS) for polygenic traits typically increases with sample size. A traditional tool for quality control and identification of significant regions has been a visual inspection of how significant and correlated genetic variants cluster within a region. However, while inspecting hundreds of regions, this subjective method can misattribute significance to some loci or neglect others that are significant.nnRESULTS: The GWAS quality score (GQS) identifies suspicious regions and prevents erroneous interpretations with an objective, quantitative and automated method. The GQS assesses all measured single nucleotide polymorphisms (SNPs) that are linked by inheritance to each other [linkage disequilibrium (LD)] and compares the significance of trait association of each SNP to its LD value for the reported index SNP. A GQS value of 1.0 ascribes a high level of confidence to the entire region and its underlying gene(s), while GQS values <1.0 indicate the need to closely inspect the outliers. We applied the GQS to published and non-published genome-wide summary statistics and report suspicious regions requiring secondary inspection while supporting the majority of reported regions from large-scale published meta-analyses.nnAVAILABILITY AND IMPLEMENTATION: The GQS code/scripts can be cloned from GitHub (https://github.com/Xswapnil/GQS/). The analyst can use whole-genome summary statistics to estimate GQS for each defined region. We also provide an online tool (http://35.227.18.38/) that gives access to the GQS. The quantitative measure of quality attributes by GQS and its visualization is an objective method that enhances the confidence of each genomic hit.nnSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37755714,
title = {An Ethical Framework for Research Using Genetic Ancestry},
author = {Anna C F Lewis and Santiago J Molina and Paul S Appelbaum and Bege Dauda and Agustin Fuentes and Stephanie M Fullerton and Nanibaa' A Garrison and Nayanika Ghosh and Robert C Green and Evelynn M Hammonds and Janina M Jeff and David S Jones and Eimear E Kenny and Peter Kraft and Madelyn Mauro and Anil P S Ori and Aaron Panofsky and Mashaal Sohail and Benjamin M Neale and Danielle S Allen},
doi = {10.1353/pbm.2023.0021},
issn = {1529-8795},
year  = {2023},
date = {2023-01-01},
journal = {Perspect Biol Med},
volume = {66},
number = {2},
pages = {225--248},
abstract = {A wide range of research uses patterns of genetic variation to infer genetic similarity between individuals, typically referred to as genetic ancestry. This research includes inference of human demographic history, understanding the genetic architecture of traits, and predicting disease risk. Researchers are not just structuring an intellectual inquiry when using genetic ancestry, they are also creating analytical frameworks with broader societal ramifications. This essay presents an ethics framework in the spirit of virtue ethics for these researchers: rather than focus on rule following, the framework is designed to build researchers' capacities to react to the ethical dimensions of their work. The authors identify one overarching principle of intellectual freedom and responsibility, noting that freedom in all its guises comes with responsibility, and they identify and define four principles that collectively uphold researchers' intellectual responsibility: truthfulness, justice and fairness, anti-racism, and public beneficence. Researchers should bring their practices into alignment with these principles, and to aid this, the authors name three common ways research practices infringe these principles, suggest a step-by-step process for aligning research choices with the principles, provide rules of thumb for achieving alignment, and give a worked case. The essay concludes by identifying support needed by researchers to act in accord with the proposed framework.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37492488,
title = {Associations between sleep health and grey matter volume in the UK Biobank cohort ( = 33 356)},
author = {Julian E Schiel and Sandra Tamm and Florian Holub and Roxana Petri and Hassan S Dashti and Katharina Domschke and Bernd Feige and Matthew O Goodman and Samuel E Jones and Jacqueline M Lane and Pietro-Luca Ratti and David W Ray and Susan Redline and Dieter Riemann and Martin K Rutter and Richa Saxena and Claire E Sexton and Masoud Tahmasian and Heming Wang and Michael N Weedon and Antoine Weihs and Simon D Kyle and Kai Spiegelhalder},
doi = {10.1093/braincomms/fcad200},
issn = {2632-1297},
year  = {2023},
date = {2023-01-01},
journal = {Brain Commun},
volume = {5},
number = {4},
pages = {fcad200},
abstract = {As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37215956,
title = {Prospective phase II trial of the dual mTORC1/2 inhibitor vistusertib for progressive or symptomatic meningiomas in persons with neurofibromatosis 2},
author = {Justin T Jordan and Christina C Orr and Raquel D Thalheimer and Josephine V Cambillo and Roberta L Beauchamp and Ghalib Shaikh and Alona Muzikansky and Anat Stemmer-Rachamimov and Marco Giovannini and Michel Kalamarides and Fred G Barker and Vijaya Ramesh and Scott R Plotkin},
doi = {10.1093/noajnl/vdad041},
issn = {2632-2498},
year  = {2023},
date = {2023-01-01},
journal = {Neurooncol Adv},
volume = {5},
number = {1},
pages = {vdad041},
abstract = {BACKGROUND: Meningiomas occur in 80% of persons with neurofibromatosis 2 (NF2) and cause significant mortality and morbidity, yet there are no effective medical treatments. -deficient tumors have constitutive activation of mammalian/mechanistic target of rapamycin (mTOR), and treatment with mTORC1 inhibitors results in growth arrest in a minority of tumors, with paradoxical activation of the mTORC2/AKT pathway. We studied the effect of vistusertib, a dual mTORC1/mTORC2 inhibitor, in NF2 patients with progressive or symptomatic meningiomas.nnMETHODS: Vistusertib was administered orally at 125 mg twice daily for 2 consecutive days each week. The primary endpoint was the imaging response in the target meningioma, defined as a volume decrease of 20% compared with the baseline. Secondary endpoints included toxicity, imaging response of nontarget tumors, quality of life, and genetic biomarkers.nnRESULTS: Eighteen participants (13 female), median age of 41 (range, 18-61) years, were enrolled. In target meningiomas, the best response was partial response (PR) in 1/18 tumors (6%) and stable disease (SD) in 17/18 tumors (94%). For all measured intracranial meningiomas and vestibular schwannomas, the best imaging response was PR in 6/59 tumors (10%) and SD in 53 (90%). Treatment-related grade 3/4 adverse events occurred in 14 (78%) participants, and 9 participants discontinued treatment due to side effects.nnCONCLUSIONS: Although the study did not meet the primary endpoint, vistusertib treatment was associated with high rates of SD in progressive NF2-related tumors. However, this dosing regimen for vistusertib was poorly tolerated. Future studies of dual mTORC inhibitors for NF2 should focus on optimizing tolerability and evaluating the relevance of tumor stability in participants.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36653354,
title = {Inflammatory and infectious upper respiratory diseases associate with 41 genomic loci and type 2 inflammation},
author = {Elmo C Saarentaus and Juha Karjalainen and Joel T Rämö and Tuomo Kiiskinen and Aki S Havulinna and Juha Mehtonen and Heidi Hautakangas and Sanni Ruotsalainen and Max Tamlander and Nina Mars and  and Sanna Toppila-Salmi and Matti Pirinen and Mitja Kurki and Samuli Ripatti and Mark Daly and Tuula Palotie and Antti Mäkitie and Aarno Palotie},
doi = {10.1038/s41467-022-33626-w},
issn = {2041-1723},
year  = {2023},
date = {2023-01-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {83},
abstract = {Inflammatory and infectious upper respiratory diseases (ICD-10: J30-J39), such as diseases of the sinonasal tract, pharynx and larynx, are growing health problems yet their genomic similarity is not known. We analyze genome-wide association to eight upper respiratory diseases (61,195 cases) among 260,405 FinnGen participants, meta-analyzing diseases in four groups based on an underlying genetic correlation structure. Aiming to understand which genetic loci contribute to susceptibility to upper respiratory diseases in general and its subtypes, we detect 41 independent genome-wide significant loci, distinguishing impact on sinonasal or pharyngeal diseases, or both. Fine-mapping implicated non-synonymous variants in nine genes, including three linked to immune-related diseases. Phenome-wide analysis implicated asthma and atopic dermatitis at sinonasal disease loci, and inflammatory bowel diseases and other immune-mediated disorders at pharyngeal disease loci. Upper respiratory diseases also genetically correlated with autoimmune diseases such as rheumatoid arthritis, autoimmune hypothyroidism, and psoriasis. Finally, we associated separate gene pathways in sinonasal and pharyngeal diseases that both contribute to type 2 immunological reaction. We show shared heritability among upper respiratory diseases that extends to several immune-mediated diseases with diverse mechanisms, such as type 2 high inflammation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36624241,
title = {Genome-wide association study of school grades identifies genetic overlap between language ability, psychopathology and creativity},
author = {Veera M Rajagopal and Andrea Ganna and Jonathan R I Coleman and Andrea Allegrini and Georgios Voloudakis and Jakob Grove and Thomas D Als and Henriette T Horsdal and Liselotte Petersen and Vivek Appadurai and Andrew Schork and Alfonso Buil and Cynthia M Bulik and Jonas Bybjerg-Grauholm and Marie Bækvad-Hansen and David M Hougaard and Ole Mors and Merete Nordentoft and Thomas Werge and  and Preben Bo Mortensen and Gerome Breen and Panos Roussos and Robert Plomin and Esben Agerbo and Anders D Børglum and Ditte Demontis},
doi = {10.1038/s41598-022-26845-0},
issn = {2045-2322},
year  = {2023},
date = {2023-01-01},
journal = {Sci Rep},
volume = {13},
number = {1},
pages = {429},
abstract = {Cognitive functions of individuals with psychiatric disorders differ from that of the general population. Such cognitive differences often manifest early in life as differential school performance and have a strong genetic basis. Here we measured genetic predictors of school performance in 30,982 individuals in English, Danish and mathematics via a genome-wide association study (GWAS) and studied their relationship with risk for six major psychiatric disorders. When decomposing the school performance into math and language-specific performances, we observed phenotypically and genetically a strong negative correlation between math performance and risk for most psychiatric disorders. But language performance correlated positively with risk for certain disorders, especially schizophrenia, which we replicate in an independent sample (n = 4547). We also found that the genetic variants relating to increased risk for schizophrenia and better language performance are overrepresented in individuals involved in creative professions (n = 2953) compared to the general population (n = 164,622). The findings together suggest that language ability, creativity and psychopathology might stem from overlapping genetic roots.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36059087,
title = {Infusion timing and sleep habits of adults receiving home parenteral and enteral nutrition: A patient-oriented survey study},
author = {Hassan S Dashti and Jordan J Rhyner and Kris M Mogensen and Meghna Godbole and Richa Saxena and Charlene Compher and Marion F Winkler},
doi = {10.1002/jpen.2446},
issn = {1941-2444},
year  = {2023},
date = {2023-01-01},
journal = {JPEN J Parenter Enteral Nutr},
volume = {47},
number = {1},
pages = {130--139},
abstract = {BACKGROUND: The emerging field of chrononutrition investigates the effects of the timing of nutritional intake on human physiology and disease pathology. It remains largely unknown when patients receiving home nutrition support routinely administer home parenteral nutrition (HPN) and/or home enteral nutrition (HEN).nnMETHODS: The present descriptive study included data collected from a patient-oriented survey designed to assess the timing of infusions and sleep habits of patients receiving HPN and HEN in the United States.nnRESULTS: A total of 100 patients were included. Patients had a mean age of 44.1 years and 81% were female. Among 73 patients supported with HPN and 27 patients supported with HEN, 86% and 44% reported overnight infusions, respectively. The median start and end times of overnight infusions were 2100 (interquartile range [IQR] = 1900-2200) and 0800 (IQR = 0700-1000), respectively, for HPN and 2000 (IQR = 1845-2137) and 0845 (IQR = 0723-1000), respectively, for HEN. Overnight infusions started 2.0 h (IQR = 1.1-3.0) and 2.0 h (IQR = 0.6-3.3) before bedtime for HPN and HEN, respectively, and stopped 12.9 min (IQR = -21.3 to 29.1) and 30.0 min (IQR = -17.1 to 79.3) after wake time for HPN and HEN, respectively. Sleep disruption because of nutrition support or urination was most common among patients receiving infusions overnight compared with those receiving infusions continuously or during the daytime.nnCONCLUSIONS: Our survey study focusing on a novel and medically relevant dimension of nutrition found that most HPN-dependent and HEN-dependent patients receive infusions overnight while asleep. Our findings suggest that overnight infusions coinciding with sleep may result in sleep and circadian disruption.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36609484,
title = {Use of serial smartphone-based assessments to characterize diverse neuropsychiatric symptom trajectories in a large trauma survivor cohort},
author = {Francesca L Beaudoin and Xinming An and Archana Basu and Yinyao Ji and Mochuan Liu and Ronald C Kessler and Robert F Doughtery and Donglin Zeng and Kenneth A Bollen and Stacey L House and Jennifer S Stevens and Thomas C Neylan and Gari D Clifford and Tanja Jovanovic and Sarah D Linnstaedt and Laura T Germine and Scott L Rauch and John P Haran and Alan B Storrow and Christopher Lewandowski and Paul I Musey and Phyllis L Hendry and Sophia Sheikh and Christopher W Jones and Brittany E Punches and Michael C Kurz and Robert A Swor and Vishnu P Murty and Meghan E McGrath and Lauren A Hudak and Jose L Pascual and Elizabeth M Datner and Anna M Chang and Claire Pearson and David A Peak and Roland C Merchant and Robert M Domeier and Niels K Rathlev and Brian J O' Neil and Paulina Sergot and Leon D Sanchez and Steven E Bruce and Justin T Baker and Jutta Joormann and Mark W Miller and Robert H Pietrzak and Deanna M Barch and Diego A Pizzagalli and John F Sheridan and Jordan W Smoller and Steven E Harte and James M Elliott and Karestan C Koenen and Kerry J Ressler and Samuel A McLean},
doi = {10.1038/s41398-022-02289-y},
issn = {2158-3188},
year  = {2023},
date = {2023-01-01},
journal = {Transl Psychiatry},
volume = {13},
number = {1},
pages = {4},
abstract = {The authors sought to characterize adverse posttraumatic neuropsychiatric sequelae (APNS) symptom trajectories across ten symptom domains (pain, depression, sleep, nightmares, avoidance, re-experiencing, anxiety, hyperarousal, somatic, and mental/fatigue symptoms) in a large, diverse, understudied sample of motor vehicle collision (MVC) survivors. More than two thousand MVC survivors were enrolled in the emergency department (ED) and completed a rotating battery of brief smartphone-based surveys over a 2-month period. Measurement models developed from survey item responses were used in latent growth curve/mixture modeling to characterize homogeneous symptom trajectories. Associations between individual trajectories and pre-trauma and peritraumatic characteristics and traditional outcomes were compared, along with associations within and between trajectories. APNS across all ten symptom domains were common in the first two months after trauma. Many risk factors and associations with high symptom burden trajectories were shared across domains. Both across and within traditional diagnostic boundaries, APNS trajectory intercepts, and slopes were substantially correlated. Across all domains, symptom severity in the immediate aftermath of trauma (trajectory intercepts) had the greatest influence on the outcome. An interactive data visualization tool was developed to allow readers to explore relationships of interest between individual characteristics, symptom trajectories, and traditional outcomes ( http://itr.med.unc.edu/aurora/parcoord/ ). Individuals presenting to the ED after MVC commonly experience a broad constellation of adverse posttraumatic symptoms. Many risk factors for diverse APNS are shared. Individuals diagnosed with a single traditional outcome should be screened for others. The utility of multidimensional categorizations that characterize individuals across traditional diagnostic domains should be explored.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36915374,
title = {Disease-specific differences in gene expression, mitochondrial function and mitochondria-endoplasmic reticulum interactions in iPSC-derived cerebral organoids and cortical neurons in schizophrenia and bipolar disorder},
author = {Annie Kathuria and Kara Lopez-Lengowski and Donna McPhie and Bruce M Cohen and Rakesh Karmacharya},
doi = {10.1007/s44192-023-00031-8},
issn = {2731-4383},
year  = {2023},
date = {2023-01-01},
journal = {Discov Ment Health},
volume = {3},
number = {1},
pages = {8},
abstract = {We compared transcriptomic profiles of cerebral organoids differentiated from induced pluripotent stem cells of eight schizophrenia and eight bipolar disorder patients to identify genes that were differentially expressed in cerebral organoids between two disorders. Gene ontology analysis showed relative up-regulation in schizophrenia organoids of genes related to response to cytokines, antigen binding and clathrin-coated vesicles, while showing up-regulation in bipolar disorder of genes involved in calcium binding. Gene set enrichment analysis revealed enrichment in schizophrenia of genes involved in mitochondrial and oxidative phosphorylation while showing enrichment in bipolar disorder of genes involved in long term potentiation and neuro-transporters. We compared mitochondrial function in cerebral organoids from schizophrenia and bipolar disorder subjects and found that while schizophrenia organoids showed deficits in basal oxygen consumption rate and ATP production when compared to healthy control organoids, while bipolar disorder organoids did not show these deficits. Gene ontology analyses also revealed enrichment in bipolar disorder of genes in ion binding and regulation of transport. Experiments examining the interaction between mitochondria and endoplasmic reticulum in cortical neurons from bipolar disorder subjects showed a significantly lower number of contact sites between mitochondria and endoplasmic reticulum when compared to cortical neurons from schizophrenia patients. These results point to disease-specific deficits in mitochondrial respiration in schizophrenia and in mitochondrial-endoplasmic reticulum interactions in bipolar disorder.nnSUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s44192-023-00031-8.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36182088,
title = {Concordance in Child-Parent Reporting of Social Victimization Experiences in the Adolescent Brain Cognitive Development Study},
author = {Judy T Tang and Altaf Saadi and Erin C Dunn and Kristen Choi},
doi = {10.1016/j.acap.2022.09.018},
issn = {1876-2867},
year  = {2023},
date = {2023-01-01},
journal = {Acad Pediatr},
volume = {23},
number = {4},
pages = {747--754},
abstract = {OBJECTIVE: To investigate child-parent concordance in reporting social victimization experiences and whether concordance was associated with child behavioral symptoms.nnMETHODS: This was an observational study with data from the Adolescent Brain Cognitive Development study. The analytic sample was 11,235 9- or 10-year-old children from the United States. Exposure variables were demographic and protective factors (child perceptions of parental relationships, school protective factors, neighborhood safety). The outcome was parent-child concordance on 6 domains of child social victimization: conventional crime, peer victimization, witnessing violence, internet victimization, school victimization, and gun violence. Child behavior symptoms were measured using the Child Behavior Checklist.nnRESULTS: Exposure to social victimization was low (9% of the sample). Concordance ranged from 18% to 50%. The highest levels of concordance were observed for conventional crime (k = 0.48, P < .001) and witnessing violence (k = 0.48, P < .001). Parents' perceptions of greater neighborhood safety was associated with lower odds of concordant conventional crime (odds ratio [OR] = 0.92, 95% confidence interval [CI] 0.86-0.99) and witnessing violence (OR = 0.92, 95% CI0.84-0.99). Concordance was associated with more internalizing/externalizing behaviors.nnCONCLUSIONS: Parents under-report social victimization in relation to children. Concordance in reporting social victimization may be an indicator of the severity of experiences, underscoring the need to consider child reports when screening for adversity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36563697,
title = {Machine learning to assess coronary artery disease status-is it helpful?},
author = {Puneet Batra and Amit V Khera},
doi = {10.1016/S0140-6736(22)02584-3},
issn = {1474-547X},
year  = {2023},
date = {2023-01-01},
journal = {Lancet},
volume = {401},
number = {10372},
pages = {173--175},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36516523,
title = {Associations among acute and chronic musculoskeletal pain, sleep duration, and C-reactive protein (CRP): A cross-sectional study of the UK biobank dataset},
author = {Sierra Hodges and Seyhmus Guler and Valeria Sacca and Mark Vangel and Scott Orr and Edward Pace-Schott and Ya Wen and Tian Ge and Jian Kong},
doi = {10.1016/j.sleep.2022.11.013},
issn = {1878-5506},
year  = {2023},
date = {2023-01-01},
journal = {Sleep Med},
volume = {101},
pages = {393--400},
abstract = {Both musculoskeletal pain and sleep disturbances are major health problems worldwide. Literature suggests that the two are reciprocally related and both may be associated with changes in C-reactive protein (CRP) levels. However, the relationships among musculoskeletal pain, sleep duration, and CRP remain unclear. In this cross-sectional study, we investigated the relationship between acute and chronic musculoskeletal pain, sleep, and inflammation using the data from the initial visit of the UK Biobank. 17,642 individuals with chronic musculoskeletal pain, 11,962 individuals with acute musculoskeletal pain, and 29,604 pain-free controls were included in the analysis. In addition, we validated the findings using data from the second visit assessment of the UK Biobank. We found that 1) chronic pain was associated with higher CRP levels compared to both acute pain and the pain-free controls; 2) chronic pain was associated with a lower sleep score (a measurement of sleep patterns), compared to acute pain and the pain-free controls; and acute pain was associated with lower sleep scores compared to the controls; 3) there was a significant negative association between the sleep score and CRP; 4) CRP may partially mediate the association between chronic pain and decreased sleep score. However, the effect size of the mediation was rather small, and the pathophysiological significance remains uncertain. Further validation is needed. These findings were partly replicated in the UK Biobank second visit assessment cohort with a smaller sample size. Our findings, which are based on the large UK Biobank dataset, support the interplay between musculoskeletal pain, sleep patterns, and the potential mediating role of CRP on this reciprocal relationship.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36563689,
title = {Small-molecule screen reveals pathways that regulate C4 secretion in stem cell-derived astrocytes},
author = {Francesca Rapino and Ted Natoli and Francesco Limone and Erin O'Connor and Jack Blank and Matthew Tegtmeyer and William Chen and Erika Norabuena and Juhi Narula and Dane Hazelbaker and Gabriella Angelini and Lindy Barrett and Alison O'Neil and Ursula K Beattie and Jessica M Thanos and Heather de Rivera and Steven D Sheridan and Roy H Perlis and Steven A McCarroll and Beth Stevens and Aravind Subramanian and Ralda Nehme and Lee L Rubin},
doi = {10.1016/j.stemcr.2022.11.018},
issn = {2213-6711},
year  = {2023},
date = {2023-01-01},
journal = {Stem Cell Reports},
volume = {18},
number = {1},
pages = {237--253},
abstract = {In the brain, the complement system plays a crucial role in the immune response and in synaptic elimination during normal development and disease. Here, we sought to identify pathways that modulate the production of complement component 4 (C4), recently associated with an increased risk of schizophrenia. To design a disease-relevant assay, we first developed a rapid and robust 3D protocol capable of producing large numbers of astrocytes from pluripotent cells. Transcriptional profiling of these astrocytes confirmed the homogeneity of this population of dorsal fetal-like astrocytes. Using a novel ELISA-based small-molecule screen, we identified epigenetic regulators, as well as inhibitors of intracellular signaling pathways, able to modulate C4 secretion from astrocytes. We then built a connectivity map to predict and validate additional key regulatory pathways, including one involving c-Jun-kinase. This work provides a foundation for developing therapies for CNS diseases involving the complement cascade.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36949957,
title = {mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease},
author = {Seyedeh M Zekavat and Vanesa Viana-Huete and Nuria Matesanz and Saman Doroodgar Jorshery and María A Zuriaga and Md Mesbah Uddin and Mark Trinder and Kaavya Paruchuri and Virginia Zorita and Alba Ferrer-Pérez and Marta Amorós-Pérez and Paolo Kunderfranco and Roberta Carriero and Carolina M Greco and Alejandra Aroca-Crevillen and Andrés Hidalgo and Scott M Damrauer and Christie M Ballantyne and Abhishek Niroula and Christopher J Gibson and James Pirruccello and Gabriel Griffin and Benjamin L Ebert and Peter Libby and Valentín Fuster and Hongyu Zhao and Marzyeh Ghassemi and Pradeep Natarajan and Alexander G Bick and José J Fuster and Derek Klarin},
doi = {10.1038/s44161-022-00206-6},
issn = {2731-0590},
year  = {2023},
date = {2023-01-01},
journal = {Nat Cardiovasc Res},
volume = {2},
pages = {144--158},
abstract = {Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as  and . To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone -/- chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13-weeks post-grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries, and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36456078,
title = {Direct and Indirect Effects in Trio Studies: You Don't Know What You're Missing},
author = {Dongmei Yu and Jeremiah M Scharf},
doi = {10.1016/j.biopsych.2022.10.004},
issn = {1873-2402},
year  = {2023},
date = {2023-01-01},
urldate = {2023-01-01},
journal = {Biol Psychiatry},
volume = {93},
number = {1},
pages = {6--7},
abstract = {Direct and Indirect Effects in Trio Studies: You Don't Know What You're Missing},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid37158703,
title = {How do experts in psychiatric genetics view the clinical utility of polygenic risk scores for schizophrenia?},
author = {Tiahna Moorthy and Huyen Nguyen and Ying Chen and Jehannine Austin and Jordan W Smoller and Laura Hercher and Maya Sabatello},
doi = {10.1002/ajmg.b.32939},
issn = {1552-485X},
year  = {2023},
date = {2023-01-01},
journal = {Am J Med Genet B Neuropsychiatr Genet},
volume = {192},
number = {7-8},
pages = {161--170},
abstract = {Polygenic risk scores (PRS) are promising for identifying common variant-related inheritance for psychiatric conditions but their integration into clinical practice depends on their clinical utility and psychiatrists' understanding of PRS. Our online survey explored these issues with 276 professionals working in psychiatric genetics (RR: 19%). Overall, participants demonstrated knowledge of how to interpret PRS results. Their performance on knowledge-based questions was positively correlated with participants' self-reported familiarity with PRS (r = 0.21, p = 0.0006) although differences were not statistically significant (Wald Chi-square = 3.29, df = 1, p = 0.07). However, only 48.9% of all participants answered all knowledge questions correctly. Many participants (56.5%), especially researchers (42%), indicated having at least occasional conversations about the role of genetics in psychiatric conditions with patients and/or family members. Most participants (62.7%) indicated that PRS are not yet sufficiently robust for assessment of susceptibility to schizophrenia; most significant obstacles were low predictive power and lack of population diversity in available PRS (selected, respectively, by 53.6% and 29.3% of participants). Nevertheless, 89.8% of participants were optimistic about the use of PRS in the next 10 years, suggesting a belief that current shortcomings could be addressed. Our findings inform about the perceptions of psychiatric professionals regarding PRS and the application of PRS in psychiatry.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36724694,
title = {Initial antidepressant choice by non-psychiatrists: Learning from large-scale electronic health records},
author = {Yi-Han Sheu and Colin Magdamo and Matthew Miller and Jordan W Smoller and Deborah Blacker},
doi = {10.1016/j.genhosppsych.2022.12.004},
issn = {1873-7714},
year  = {2023},
date = {2023-01-01},
journal = {Gen Hosp Psychiatry},
volume = {81},
pages = {22--31},
abstract = {OBJECTIVES: Pharmacological treatment of depression mostly occurs in non-psychiatric settings, but the determinants of initial choice of antidepressant treatment in these settings are unclear. We investigate how non-psychiatrists choose among four antidepressant classes at first prescription (selective serotonin reuptake inhibitors [SSRI], bupropion, mirtazapine, or serotonin-norepinephrine reuptake inhibitors [SNRI]).nnMETHOD: Using electronic health records (EHRs), we included adult patients at the time of first antidepressant prescription with a co-occurring diagnosis code for a depressive disorder. We selected 64 variables based on a literature search and expert consultation, constructed the variables from either structured codes or through applying natural language processing (NLP), and modeled antidepressant choice using multinomial logistic regression, using SSRI as the reference class.nnRESULTS: With 47,528 patients, we observed significant associations for 36 of 64 variables. Many of these associations suggested antidepressants' known pharmacological properties/actions guided choice. For example, there was a decreased likelihood of bupropion prescription among patients with epilepsy (adjusted OR 0.49, 95%CI: 0.41-0.57, p < 0.001), and an increased likelihood of mirtazapine prescription among patients with insomnia (adjusted OR 1.59, 95%CI: 1.40-1.80, p < 0.001).nnCONCLUSIONS: Broadly speaking, non-psychiatrists' selection of antidepressant class appears to be at least in part guided by clinically relevant pharmacological considerations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36711677,
title = {Nuclear genetic control of mtDNA copy number and heteroplasmy in humans},
author = {Rahul Gupta and Masahiro Kanai and Timothy J Durham and Kristin Tsuo and Jason G McCoy and Patrick F Chinnery and Konrad J Karczewski and Sarah E Calvo and Benjamin M Neale and Vamsi K Mootha},
doi = {10.1101/2023.01.19.23284696},
year  = {2023},
date = {2023-01-01},
journal = {medRxiv},
abstract = {Human mitochondria contain a high copy number, maternally transmitted genome (mtDNA) that encodes 13 proteins required for oxidative phosphorylation. Heteroplasmy arises when multiple mtDNA variants co-exist in an individual and can exhibit complex dynamics in disease and in aging. As all proteins involved in mtDNA replication and maintenance are nuclear-encoded, heteroplasmy levels can, in principle, be under nuclear genetic control, however this has never been shown in humans. Here, we develop algorithms to quantify mtDNA copy number (mtCN) and heteroplasmy levels using blood-derived whole genome sequences from 274,832 individuals of diverse ancestry and perform GWAS to identify nuclear loci controlling these traits. After careful correction for blood cell composition, we observe that mtCN declines linearly with age and is associated with 92 independent nuclear genetic loci. We find that nearly every individual carries heteroplasmic variants that obey two key patterns: (1) heteroplasmic single nucleotide variants are somatic mutations that accumulate sharply after age 70, while (2) heteroplasmic indels are maternally transmitted as mtDNA mixtures with resulting levels influenced by 42 independent nuclear loci involved in mtDNA replication, maintenance, and novel pathways. These nuclear loci do not appear to act by mtDNA mutagenesis, but rather, likely act by conferring a replicative advantage to specific mtDNA molecules. As an illustrative example, the most common heteroplasmy we identify is a length variant carried by >50% of humans at position m.302 within a G-quadruplex known to serve as a replication switch. We find that this heteroplasmic variant exerts  -acting genetic control over mtDNA abundance and is itself under  -acting genetic control of nuclear loci encoding protein components of this regulatory switch. Our study showcases how nuclear haplotype can privilege the replication of specific mtDNA molecules to shape mtCN and heteroplasmy dynamics in the human population.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36475469,
title = {Beyond the Limits of Visual Learning: Prediction of Time From Onset From Noncontrast CT of Acute Ischemic Stroke},
author = {Yutong Chen and Ernst Mayerhofer and Livia Parodi and Andreas Harloff and Puneet Batra and Jonathan Rosand and Christopher D Anderson},
doi = {10.1161/STROKEAHA.122.041370},
issn = {1524-4628},
year  = {2023},
date = {2023-01-01},
urldate = {2023-01-01},
journal = {Stroke},
volume = {54},
number = {1},
pages = {e7--e8},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid35900144,
title = {Behavior ratings of executive functions index multiple domains of psychopathology and school functioning in child psychiatric outpatients},
author = {Alisha R Pollastri and Gina Forchelli and Pieter J Vuijk and Samantha J Stoll and Michael R Capawana and Joseph Bellitti and Ellen B Braaten and Alysa E Doyle},
doi = {10.1080/21622965.2022.2099743},
issn = {2162-2973},
year  = {2023},
date = {2023-01-01},
journal = {Appl Neuropsychol Child},
volume = {12},
number = {4},
pages = {304--317},
abstract = {Behavior rating scales of executive functions (EFs) are convenient and associate with academic and other outcomes; however, prior studies indicate limited correlations with psychometric tests of EFs. To better understand their potential for clinical utility, we examined the extent to which parent ratings on the Behavior Rating Inventory of Executive Function (BRIEF) related to psychopathology constructs and psychometric test scores in a sample of  = 692 psychiatric outpatients aged 8-17. Then, in a subsample of the youth ( = 261), we related the BRIEF, psychopathology constructs, and psychometric test scores to teacher ratings of school functioning. BRIEF scales were significantly associated with multiple types of psychopathology including ADHD, autism spectrum, mood, anxiety, conduct, oppositional defiant, and psychotic disorders. While the BRIEF showed limited associations with psychometric EF tests, its Global Executive Composite score explained additional variance in teacher-reported functioning beyond what was predicted by clinical diagnoses (additional explained variance of 9.9% in study skills) and psychometric tests (additional explained variance of 2.1% in learning problems and 4.5% in study skills). The Global Executive Composite was not significantly related to teacher-rated school functioning after psychiatric symptoms were accounted for. These findings support further investigation of the unique contribution of the BRIEF in clinical practice.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid37214416,
title = {Corrigendum: Genetic heritability as a tool to evaluate the precision of 24-hour recall dietary questionnaire variables in UK Biobank},
author = {Joanne B Cole and Kenneth E Westerman and Alisa K Manning and Jose C Florez and Joel N Hirschhorn},
doi = {10.3389/fgene.2023.1202158},
issn = {1664-8021},
year  = {2023},
date = {2023-01-01},
journal = {Front Genet},
volume = {14},
pages = {1202158},
abstract = {[This corrects the article DOI: 10.3389/fgene.2022.1070511.].},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid37234786,
title = {Corrigendum: How often is occult atrial fibrillation in cryptogenic stroke causal vs. incidental? A meta-analysis},
author = {Napasri Chaisinanunkul and Shaan Khurshid and Brian H Buck and Alejandro A Rabinstein and Christopher D Anderson and Michael D Hill and Jennifer E Fugate and Jeffrey L Saver},
doi = {10.3389/fneur.2023.1206563},
issn = {1664-2295},
year  = {2023},
date = {2023-01-01},
journal = {Front Neurol},
volume = {14},
pages = {1206563},
abstract = {[This corrects the article DOI: 10.3389/fneur.2023.1103664.].},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36689568,
title = {Interleukin-6 Receptor Polymorphism Attenuates Clonal Hematopoiesis-Mediated Coronary Artery Disease Risk Among 451 180 Individuals in the UK Biobank},
author = {Caitlyn Vlasschaert and J Brett Heimlich and Michael J Rauh and Pradeep Natarajan and Alexander G Bick},
doi = {10.1161/CIRCULATIONAHA.122.062126},
issn = {1524-4539},
year  = {2023},
date = {2023-01-01},
journal = {Circulation},
volume = {147},
number = {4},
pages = {358--360},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36254612,
title = {The Inflammation Biomarker GlycA Reflects Plasma N-Glycan Branching},
author = {Maxence Noel and Daniel I Chasman and Samia Mora and James D Otvos and Christopher D Palmer and Patrick J Parsons and Jordan W Smoller and Richard D Cummings and Robert G Mealer},
doi = {10.1093/clinchem/hvac160},
issn = {1530-8561},
year  = {2023},
date = {2023-01-01},
journal = {Clin Chem},
volume = {69},
number = {1},
pages = {80--87},
abstract = {BACKGROUND: GlycA is a nuclear magnetic resonance (NMR) signal in plasma that correlates with inflammation and cardiovascular outcomes in large data sets. The signal is thought to originate from N-acetylglucosamine (GlcNAc) residues of branched plasma N-glycans, though direct experimental evidence is limited. Trace element concentrations affect plasma glycosylation patterns and may thereby also influence GlycA.nnMETHODS: NMR GlycA signal was measured in plasma samples from 87 individuals and correlated with MALDI-MS N-glycomics and trace element analysis. We further evaluated the genetic association with GlycA at rs13107325, a single nucleotide polymorphism resulting in a missense variant within SLC39A8, a manganese transporter that influences N-glycan branching, both in our samples and existing genome-wide association studies data from 22 835 participants in the Women's Health Study (WHS).nnRESULTS: GlycA signal was correlated with both N-glycan branching (r2 ranging from 0.125-0.265; all P < 0.001) and copper concentration (r2 = 0.348, P < 0.0001). In addition, GlycA levels were associated with rs13107325 genotype in the WHS (β [standard error of the mean] = -4.66 [1.2674], P = 0.0002).nnCONCLUSIONS: These results provide the first direct experimental evidence linking the GlycA NMR signal to N-glycan branching commonly associated with acute phase reactive proteins involved in inflammation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid33880984,
title = {Prevalence and risk factors of psychiatric symptoms and diagnoses before and during the COVID-19 pandemic: findings from the ELSA-Brasil COVID-19 mental health cohort},
author = {André Russowsky Brunoni and Paulo Jeng Chian Suen and Pedro Starzynski Bacchi and Lais Boralli Razza and Izio Klein and Leonardo Afonso Dos Santos and Itamar de Souza Santos and Leandro da Costa Lane Valiengo and José Gallucci-Neto and Marina Lopes Moreno and Bianca Silva Pinto and Larissa de Cássia Silva Félix and Juliana Pereira de Sousa and Maria Carmen Viana and Pamela Marques Forte and Marcia Cristina de Altisent Oliveira Cardoso and Marcio Sommer Bittencourt and Rebeca Pelosof and Luciana Lima de Siqueira and Daniel Fatori and Helena Bellini and Priscila Vilela Silveira Bueno and Ives Cavalcante Passos and Maria Angelica Nunes and Giovanni Abrahão Salum and Sarah Bauermeister and Jordan W Smoller and Paulo Andrade Lotufo and Isabela Martins Benseñor},
doi = {10.1017/S0033291721001719},
issn = {1469-8978},
year  = {2023},
date = {2023-01-01},
journal = {Psychol Med},
volume = {53},
number = {2},
pages = {446--457},
abstract = {BACKGROUND: There is mixed evidence on increasing rates of psychiatric disorders and symptoms during the coronavirus disease 2019 (COVID-19) pandemic in 2020. We evaluated pandemic-related psychopathology and psychiatry diagnoses and their determinants in the Brazilian Longitudinal Study of Health (ELSA-Brasil) São Paulo Research Center.nnMETHODS: Between pre-pandemic ELSA-Brasil assessments in 2008-2010 (wave-1), 2012-2014 (wave-2), 2016-2018 (wave-3) and three pandemic assessments in 2020 (COVID-19 waves in May-July, July-September, and October-December), rates of common psychiatric symptoms, and depressive, anxiety, and common mental disorders (CMDs) were compared using the Clinical Interview Scheduled-Revised (CIS-R) and the Depression Anxiety Stress Scale-21 (DASS-21). Multivariable generalized linear models, adjusted by age, gender, educational level, and ethnicity identified variables associated with an elevated risk for mental disorders.nnRESULTS: In 2117 participants (mean age 62.3 years, 58.2% females), rates of CMDs and depressive disorders did not significantly change over time, oscillating from 23.5% to 21.1%, and 3.3% to 2.8%, respectively; whereas rate of anxiety disorders significantly decreased (2008-2010: 13.8%; 2016-2018: 9.8%; 2020: 8%). There was a decrease along three wave-COVID assessments for depression [ = -0.37, 99.5% confidence interval (CI) -0.50 to -0.23], anxiety ( = -0.37, 99.5% CI -0.48 to -0.26), and stress ( = -0.48, 99.5% CI -0.64 to -0.33) symptoms (all s < 0.001). Younger age, female sex, lower educational level, non-white ethnicity, and previous psychiatric disorders were associated with increased odds for psychiatric disorders, whereas self-evaluated good health and good quality of relationships with decreased risk.nnCONCLUSION: No consistent evidence of pandemic-related worsening psychopathology in our cohort was found. Indeed, psychiatric symptoms slightly decreased along 2020. Risk factors representing socioeconomic disadvantages were associated with increased odds of psychiatric disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{pmid36268164,
title = {Erratum: Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium},
author = {Lindsay Fernández-Rhodes and Mariaelisa Graff and Victoria L Buchanan and Anne E Justice and Heather M Highland and Xiuqing Guo and Wanying Zhu and Hung-Hsin Chen and Kristin L Young and Kaustubh Adhikari and Nicholette D Palmer and Jennifer E Below and Jonathan Bradfield and Alexandre C Pereira and LáShauntá Glover and Daeeun Kim and Adam G Lilly and Poojan Shrestha and Alvin G Thomas and Xinruo Zhang and Minhui Chen and Charleston W K Chiang and Sara Pulit and Andrea Horimoto and Jose E Krieger and Marta Guindo-Martínez and Michael Preuss and Claudia Schumann and Roelof A J Smit and Gabriela Torres-Mejía and Victor Acuña-Alonzo and Gabriel Bedoya and Maria-Cátira Bortolini and Samuel Canizales-Quinteros and Carla Gallo and Rolando González-José and Giovanni Poletti and Francisco Rothhammer and Hakon Hakonarson and Robert Igo and Sharon G Adler and Sudha K Iyengar and Susanne B Nicholas and Stephanie M Gogarten and Carmen R Isasi and George Papnicolaou and Adrienne M Stilp and Qibin Qi and Minjung Kho and Jennifer A Smith and Carl D Langefeld and Lynne Wagenknecht and Roberta Mckean-Cowdin and Xiaoyi Raymond Gao and Darryl Nousome and David V Conti and Ye Feng and Matthew A Allison and Zorayr Arzumanyan and Thomas A Buchanan and Yii-Der Ida Chen and Pauline M Genter and Mark O Goodarzi and Yang Hai and Willa Hsueh and Eli Ipp and Fouad R Kandeel and Kelvin Lam and Xiaohui Li and Jerry L Nadler and Leslie J Raffel and Kathryn Roll and Kevin Sandow and Jingyi Tan and Kent D Taylor and Anny H Xiang and Jie Yao and Astride Audirac-Chalifour and Jose de Jesus Peralta Romero and Fernando Hartwig and Bernando Horta and John Blangero and Joanne E Curran and Ravindranath Duggirala and Donna E Lehman and Sobha Puppala and Laura Fejerman and Esther M John and Carlos Aguilar-Salinas and Noël P Burtt and Jose C Florez and Humberto García-Ortíz and Clicerio González-Villalpando and Josep Mercader and Lorena Orozco and Teresa Tusié-Luna and Estela Blanco and Sheila Gahagan and Nancy J Cox and Craig Hanis and Nancy F Butte and Shelley A Cole and Anthony G Comuzzie and V Saroja Voruganti and Rebecca Rohde and Yujie Wang and Tamar Sofer and Elad Ziv and Struan F A Grant and Andres Ruiz-Linares and Jerome I Rotter and Christopher A Haiman and Esteban J Parra and Miguel Cruz and Ruth J F Loos and Kari E North},
doi = {10.1016/j.xhgg.2022.100149},
issn = {2666-2477},
year  = {2023},
date = {2023-01-01},
journal = {HGG Adv},
volume = {4},
number = {1},
pages = {100149},
abstract = {[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.].},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{pmid36747741,
title = {Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals},
author = {Hang Zhou and Rachel L Kember and Joseph D Deak and Heng Xu and Sylvanus Toikumo and Kai Yuan and Penelope A Lind and Leila Farajzadeh and Lu Wang and Alexander S Hatoum and Jessica Johnson and Hyunjoon Lee and Travis T Mallard and Jiayi Xu and Keira J A Johnston and Emma C Johnson and Marco Galimberti and Cecilia Dao and Daniel F Levey and Cassie Overstreet and Enda M Byrne and Nathan A Gillespie and Scott Gordon and Ian B Hickie and John B Whitfield and Ke Xu and Hongyu Zhao and Laura M Huckins and Lea K Davis and Sandra Sanchez-Roige and Pamela A F Madden and Andrew C Heath and Sarah E Medland and Nicholas G Martin and Tian Ge and Jordan W Smoller and David M Hougaard and Anders D Børglum and Ditte Demontis and John H Krystal and J Michael Gaziano and Howard J Edenberg and Arpana Agrawal and  and Amy C Justice and Murray B Stein and Henry R Kranzler and Joel Gelernter},
doi = {10.1101/2023.01.24.23284960},
year  = {2023},
date = {2023-01-01},
journal = {medRxiv},
abstract = {Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{pmid36685559,
title = {CRISPR-Cas9-AAV versus lentivector transduction for genome modification of X-linked severe combined immunodeficiency hematopoietic stem cells},
author = {Julie Brault and Taylor Liu and Siyuan Liu and Amanda Lawson and Uimook Choi and Nikita Kozhushko and Vera Bzhilyanskaya and Mara Pavel-Dinu and Ronald J Meis and Michael A Eckhaus and Sandra S Burkett and Marita Bosticardo and Benjamin P Kleinstiver and Luigi D Notarangelo and Cicera R Lazzarotto and Shengdar Q Tsai and Xiaolin Wu and Gary A Dahl and Matthew H Porteus and Harry L Malech and Suk See De Ravin},
doi = {10.3389/fimmu.2022.1067417},
issn = {1664-3224},
year  = {2022},
date = {2022-01-01},
journal = {Front Immunol},
volume = {13},
pages = {1067417},
abstract = {INTRODUCTION:  gene therapy for treatment of Inborn errors of Immunity (IEIs) have demonstrated significant clinical benefit in multiple Phase I/II clinical trials. Current approaches rely on engineered retroviral vectors to randomly integrate copy(s) of gene-of-interest in autologous hematopoietic stem/progenitor cells (HSPCs) genome permanently to provide gene function in transduced HSPCs and their progenies. To circumvent concerns related to potential genotoxicities due to the random vector integrations in HSPCs, targeted correction with CRISPR-Cas9-based genome editing offers improved precision for functional correction of multiple IEIs.nnMETHODS: We compare the two approaches for integration of  transgene for functional correction of HSPCs from patients with X-linked Severe Combined Immunodeficiency (SCID-X1 or XSCID); delivery  current clinical lentivector (LV)- versus targeted insertion (TI) of  homology-directed repair (HDR) when using an adeno-associated virus (AAV)- donor following double-strand DNA break at the endogenous  locus.nnRESULTS AND DISCUSSION:  differentiation of LV- or TI-treated XSCID HSPCs similarly overcome differentiation block into Pre-T-I and Pre-T-II lymphocytes but we observed significantly superior development of NK cells when corrected by TI (40.7% versus 4.1%, p = 0.0099). Transplants into immunodeficient mice demonstrated robust engraftment (8.1% and 23.3% in bone marrow) for LV- and TI- HSPCs with efficient T cell development following TI- in all four patients' HSPCs. Extensive specificity analysis of CRISPR-Cas9 editing with rhAmpSeq covering 82 predicted off-target sites found no evidence of indels in edited cells before () or following transplant, in stark contrast to LV's non-targeted vector integration sites. Together, the improved efficiency and safety of  correction  CRISPR-Cas9-based TI approach provides a strong rationale for a clinical trial for treatment of XSCID patients.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid36685884,
title = {Genetic heritability as a tool to evaluate the precision of 24-hour recall dietary questionnaire variables in UK Biobank},
author = {Joanne B Cole and Kenneth E Westerman and Alisa K Manning and Jose C Florez and Joel N Hirschhorn},
doi = {10.3389/fgene.2022.1070511},
issn = {1664-8021},
year  = {2022},
date = {2022-01-01},
journal = {Front Genet},
volume = {13},
pages = {1070511},
abstract = {A variety of statistical approaches in nutritional epidemiology have been developed to enhance the precision of dietary variables derived from longitudinal questionnaires. Correlation with biomarkers is often used to assess the relative validity of these different approaches, however, validated biomarkers do not always exist and are costly and laborious to collect. We present a novel high-throughput approach which utilizes the modest but importantly non-zero influence of genetic variation on variation in dietary intake to compare different statistical transformations of dietary variables. Specifically, we compare the heritability of crude averages with Empirical Bayes weighted averages for 302 correlated dietary variables from multiple 24-hour recall questionnaires in 177 K individuals in UK Biobank. Overall, the crude averages for frequency of consumption are more heritable than their Empirical Bayes counterparts only when the reliability of that item across questionnaires is high (measured by intra-class correlation), otherwise, the Empirical Bayes approach (for both unreliably measured frequencies and for average quantities independent of reliability) leads to higher heritability estimates. We also find that the more heritable versions of each dietary variable lead to stronger underlying statistical associations with specific genetic loci, many of which have well-known mechanisms, further supporting heritability as an alternative metric for relative validity in nutritional epidemiology and beyond.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}