- Physical performance and plasma metabolic profile as potential prognostic factors in metastatic lung cancer patientson July 26, 2024
CONCLUSION: These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism.
- Comorbidity Profiles of Posttraumatic Stress Disorder Across the Medical Phenomeon July 25, 2024
CONCLUSIONS: 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 electronic health records.
- Integrative Metabolomics Differentiate Coronary Artery Disease, Peripheral Artery Disease, and Venous Thromboembolism Riskson July 25, 2024
CONCLUSIONS: While common vascular conditions are associated with overlapping metabolomic profiles, MR prioritized the role of specific lipoprotein species for potential pharmacological targets to maximize benefits in both arterial and venous beds.
- Brain Care Score and Neuroimaging Markers of Brain Health in Asymptomatic Middle-Age Personson July 25, 2024
OBJECTIVES: To investigate associations between health-related behaviors as measured using the Brain Care Score (BCS) and neuroimaging markers of white matter injury.
- Polygenic risk scores as a marker for epilepsy risk across lifetime and after unspecified seizure eventson July 25, 2024
A diagnosis of epilepsy has significant consequences for an individual but is often challenging in clinical practice. Novel biomarkers are thus greatly needed. Here, we investigated how common genetic factors (epilepsy polygenic risk scores, [PRSs]) influence epilepsy risk in detailed longitudinal electronic health records (EHRs) of > 700k Finns and Estonians. We found that a high genetic generalized epilepsy PRS (PRS(GGE)) increased risk for genetic generalized epilepsy (GGE) (hazard ratio […]
- High incidence and geographic distribution of cleft palate cases in Finland are associated with a regulatory variant in IRF6on July 23, 2024
In Finland the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We performed a genome-wide association study for orofacial clefts, which include CL/P and CP, in the Finnish population. We identified rs570516915, a single nucleotide polymorphism that is highly enriched in Finns and Estonians, as being strongly associated with […]
- Autoimmune hypothyroidism GWAS reveals independent autoimmune and thyroid-specific contributions and an inverse relation with cancer riskon July 23, 2024
The high prevalence of autoimmune hypothyroidism (AIHT) - more than 5% in human populations - provides a unique opportunity to unlock the most complete picture to date of genetic loci that underlie systemic and organ-specific autoimmunity. Using a meta-analysis of 81,718 AIHT cases in FinnGen and the UK Biobank, we dissect associations along axes of thyroid dysfunction and autoimmunity. This largest-to-date scan of hypothyroidism identifies 418 independent associations (p
- Unexpected dearomatization of N-protected 5-aminopyrazoles at ambient temperature: a simple route to highly functionalized pyrazolineson July 23, 2024
We present a new strategy for the dearomatized hydroxylation of 5-aminopyrazoles using a hypervalent iodine reagent at room temperature. This method produces a series of 4-hydroxy-5-iminopyrazolines with good to excellent yields within 2 hours. Additionally, we demonstrate a domino reaction for the synthesis of 4-hydroxy-pyrazolones. Mechanistic studies indicate that the dearomatization proceeds through a cationic intermediate.
- Hemoglobin A1c Genetics and Disparities in Risk of Diabetic Retinopathy in Individuals of Genetically Inferred African American/African British and European Ancestrieson July 23, 2024
CONCLUSIONS: Genetic effects need to be considered to personalize HbA1c targets and improve outcomes of people with diabetes from diverse ancestries.
- Complex trait susceptibilities and population diversity in a sample of 4,145 Russianson July 23, 2024
The population of Russia consists of more than 150 local ethnicities. The ethnic diversity and geographic origins, which extend from eastern Europe to Asia, make the population uniquely positioned to investigate the shared properties of inherited disease risks between European and Asian ancestries. We present the analysis of genetic and phenotypic data from a cohort of 4,145 individuals collected in three metro areas in western Russia. We show the presence of multiple admixed genetic ancestry...
- Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephalyon July 22, 2024
CONCLUSION: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.
- Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhageon July 22, 2024
Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. Functional annotation analysis indicated candidate genes HAND2, TBX3 and RAP2C/FRMD7 at three loci and showed that at each locus, associated variants were located within […]
- Click editing enables programmable genome writing using DNA polymerases and HUH endonucleaseson July 22, 2024
Genome editing technologies based on DNA-dependent polymerases (DDPs) could offer several benefits compared with other types of editors to install diverse edits. Here, we develop click editing, a genome writing platform that couples the advantageous properties of DDPs with RNA-programmable nickases 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 with...
- Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trialon July 22, 2024
CONCLUSIONS: Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivariable model, and the large sample […]
- Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorderson July 21, 2024
CONCLUSION: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.
- Advancing Genetic Testing in Kidney Diseases: Report From a National Kidney Foundation Working Groupon July 21, 2024
About 37 million people in the United States have chronic kidney disease, a disease that encompasses diseases of multiple causes. About 10% or more of kidney diseases in adults and about 70% of selected chronic kidney diseases in children are expected to be explained by genetic causes. Despite the advances in genetic testing and an increasing understanding of the genetic bases of certain kidney diseases, genetic testing in nephrology lags behind other medical fields. More understanding of the...
- Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendationson July 20, 2024
CONCLUSION: A small number of variants per proband reached PP3_Strong and PP3_Moderate in 3,424 disease-associated genes, and though not the intended use of the recommendations, also genome-wide. Use of PP3/BP4 evidence as recommended from calibrated computational prediction tools in the clinical diagnostic laboratory is unlikely to inappropriately contribute to the classification of an excessive number of variants as Pathogenic or Likely Pathogenic by ACMG/AMP rules.
- Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiencyon July 20, 2024
Heterozygous loss-of-function mutations in the GRN gene are a major cause of hereditary frontotemporal dementia. The mechanisms linking frontotemporal dementia pathogenesis to progranulin deficiency are not well understood, and there is currently no treatment. Our strategy to prevent the onset and progression of frontotemporal dementia in patients with GRN mutations is to utilize small molecule positive regulators of GRN expression to boost progranulin levels from the remaining functional GRN...
- Genetic testing in early-onset atrial fibrillationon July 19, 2024
Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among...
- Reporting guidelines for precision medicine research of clinical relevance: the BePRECISE checkliston July 19, 2024
Precision medicine should aspire to reduce error and improve accuracy in medical and health recommendations by comparison with contemporary practice, while maintaining safety and cost-effectiveness. The etiology, clinical manifestation and prognosis of diseases such as obesity, diabetes, cardiovascular disease, kidney disease and fatty liver disease are heterogeneous. Without standardized reporting, this heterogeneity, combined with the diversity of research tools used in precision medicine...
- Precision treatment of beta-cell monogenic diabetes: a systematic reviewon July 18, 2024
CONCLUSION: There is limited evidence, and with moderate or serious risk of bias, to guide monogenic diabetes treatment. Further evidence is needed to examine the optimum treatment in monogenic subtypes.
- Chemical genetic screens reveal defective lysosomal trafficking as synthetic lethal with NF1 losson July 17, 2024
Neurofibromatosis type 1, a genetic disorder caused by germline mutations in NF1, predisposes patients to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas, and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors such as glioblastoma (GBM), melanoma, […]
- Burden of illness and mortality in men with Adrenomyeloneuropathy: a retrospective cohort studyon July 17, 2024
CONCLUSION: AMN imposes a substantial and underrecognized health burden on men, with higher healthcare utilization, greater medical comorbidity, higher mortality rates, and younger age at death.
- Evaluating predictors of kinase activity of STK11 variants identified in primary human non-small cell lung cancerson July 16, 2024
Critical evaluation of computational tools for predicting variant effects is important considering their increased use in disease diagnosis and driving molecular discoveries. In the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, a dataset of 28 STK11 rare variants (27 missense, 1 single amino acid deletion), identified in primary non-small cell lung cancer biopsies, was experimentally assayed to characterize computational methods from four participating […]
- Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromeson July 16, 2024
Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the […]
- Research Letter: Characterizing spin in psychiatric clinical research literature using large language modelson July 15, 2024
CONCLUSIONS AND RELEVANCE: A substantial subset of psychiatric intervention abstracts in high-impact journals may contain results presented in a potentially misleading way, with the potential to impact clinical practice. The success in automating spin detection via large language models may facilitate identification and revision to minimize spin in future publications.
- Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signalingon July 15, 2024
The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58...
- Transcriptome-wide characterization of genetic perturbationson July 15, 2024
Single cell CRISPR screens such as Perturb-seq enable transcriptomic profiling of genetic perturbations at scale. However, the data produced by these screens are often noisy due to cost and technical constraints, limiting power to detect true effects with conventional differential expression analyses. Here, we introduce TRanscriptome-wide Analysis of Differential Expression (TRADE), a statistical framework which estimates the transcriptome-wide distribution of true differential expression...
- Associations between positive childhood experiences (PCEs), discrimination, and internalizing/externalizing in pre-adolescentson July 14, 2024
CONCLUSIONS: Results of this national study suggest cumulative discrimination can exert emotional/behavioral health harm among youth. PCEs were independently associated with reduced behavioral symptoms. There is a need for further research on how to prevent discrimination and bolster PCEs by targeting upstream social inequities in communities.
- Organocatalytic Dearomatization of 5-Aminopyrazoles: Synthesis of 4-Hydroxypyrazolineson July 11, 2024
Dearomatization is a fundamental chemical reaction that affords complex three-dimensional heterocyclic frameworks. We disclose the first organocatalytic dearomatization of 5-aminopyrazoles, which yields a range of structurally diversified C4-hydroxylated pyrazolines with yields of ≤95% in
- De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndromeon July 11, 2024
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes¹. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome². We identify an 18 […]
- A global initiative to deliver precision health in diabeteson July 11, 2024
No abstract
- Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discoveryon July 11, 2024
CONCLUSIONS: Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.
- Heterogeneity in Antidepressant Treatment and Major Depressive Disorder Outcomes Among Clinicianson July 10, 2024
CONCLUSIONS AND RELEVANCE: Groups of clinicians treating individuals diagnosed with major depressive disorder exhibit marked differences in prescribing patterns as well as longitudinal patient outcomes defined by electronic health records. Incorporating these group identifiers yielded similar prediction to more complex models incorporating individual codes, suggesting the importance of considering treatment context in efforts at risk stratification.
- Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencingon July 9, 2024
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and […]
- Early B-cell transcription factor-2 defect as a novel cause of lipodystrophy: disruption of the adipose tissue character and integrityon July 9, 2024
We report a novel cause of partial lipodystrophy associated with early B cell factor 2 (EBF2) nonsense variant (EBF2 8:26033143 C>A, c.493G>T, p.E165X) in a patient with an atypical form of partial lipodystrophy. The patient presented with progressive adipose tissue loss and metabolic deterioration at pre-pubertal age. In vitro and in vivo disease modeling demonstrates that the EBF2 variant impairs adipogenesis, causing excess accumulation of undifferentiated CD34^(+) cells, extracellular […]
- Genetic Variation and Stroke Recovery: The STRONG Studyon July 9, 2024
CONCLUSIONS: This study identified genetic associations with cognitive function, depression, and PTSD 1 year poststroke. Genetic susceptibility to PTSD and depressive symptoms varied according to the amount of poststroke stress, underscoring the critical role of lived experiences in recovery. Together, the results suggest that genetic association studies provide insights into the biology of stroke recovery in humans.
- Publisher Correction: Understanding the genetic complexity of puberty timing across the allele frequency spectrumon July 9, 2024
No abstract
- Correspondence on "Comparison of literature mining tools for variant classification: Through the lens of 50 RYR1 variants" by Wermers et alon July 8, 2024
No abstract
- Applications, limitations and advancements of ultra-low-field magnetic resonance imaging: A scoping reviewon July 8, 2024
CONCLUSION: This review summarizes the potential of ULF-MRI. The technology's adaptability in intensive care unit settings and its diverse clinical and surgical applications, while accounting for SNR and resolution limitations, highlight its significance, especially in resource-limited settings. Technological advancements, alongside expert recommendations, pave the way for refining and expanding ULF-MRI's utility. However, adequate training is crucial for widespread utilization.
- CircHTT(2,3,4,5,6) - co-evolving with the HTT CAG-repeat tract - modulates Huntington's disease phenotypeson July 8, 2024
Circular RNA (circRNA) molecules have critical functions during brain development and in brain-related disorders. Here, we identified and validated a circRNA, circHTT(2,3,4,5,6), stemming from the Huntington's disease (HD) gene locus that is most abundant in the central nervous system (CNS). We uncovered its evolutionary conservation in diverse mammalian species, and a correlation between circHTT(2,3,4,5,6) levels and the length of the CAG-repeat tract in exon-1 of HTT in human and mouse HD...
- Exploring the complexity of systemic sclerosis etiology by trio whole genome sequencingon July 6, 2024
Systemic sclerosis (SSc) is a heterogeneous rare autoimmune fibrosing disorder affecting connective tissue. The etiology of systemic sclerosis is largely unknown and many genes have been suggested as susceptibility loci of modest impact by genome-wide association study (GWAS). Multiple factors can contribute to the pathological process of the disease, which makes it more difficult to identify possible disease-causing genetic alterations. In this study, we have applied whole genome sequencing...
- Towards Standardizing Nomenclature in Huntington's Disease Researchon July 5, 2024
The field of Huntington's disease research covers many different scientific disciplines, from molecular biology all the way through to clinical practice, and as our understanding of the disease has progressed over the decades, a great deal of different terminology has accrued. The field is also renowned for its collaborative spirit and use of standardized reagents, assays, datasets, models, and clinical measures, so the use of standardized terms is especially important. We have set out to...
- Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophyon July 4, 2024
OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease.
- Principled distillation of UK Biobank phenotype data reveals underlying structure in human variationon July 4, 2024
Data within biobanks capture broad yet detailed indices of human variation, but biobank-wide insights can be difficult to extract due to complexity and scale. Here, using large-scale factor analysis, we distill hundreds of variables (diagnoses, assessments and survey items) into 35 latent constructs, using data from unrelated individuals with predominantly estimated European genetic ancestry in UK Biobank. These factors recapitulate known disease classifications, disentangle elements of...
- Association of genetic risk, lifestyle, and their interaction with obesity and obesity-related morbiditieson July 3, 2024
The extent to which modifiable lifestyle factors offset the determined genetic risk of obesity and obesity-related morbidities remains unknown. We explored how the interaction between genetic and lifestyle factors influences the risk of obesity and obesity-related morbidities. The polygenic score for body mass index was calculated to quantify inherited susceptibility to obesity in 338,645 UK Biobank European participants, and a composite lifestyle score was derived from five obesogenic […]
- Improving transparency of computational tools for variant effect predictionon July 2, 2024
No abstract
- Parental Perspectives Regarding the Return of Genomic Research Results in Neurodevelopmental Disorders in South Africa: Anticipated Impact and Preferenceson July 1, 2024
Few policies and little research exist regarding the disclosure of genomic results to research participants in Africa. As understanding participant preferences would be pivotal to the success of the feedback process, this study set out to address this issue by engaging with enrolled participants from an ongoing genomics research project on neurodevelopmental disorders with the aim to assess the anticipated impact of receiving pertinent results and explore the preferences for feedback in a...
- Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndromeon July 1, 2024
Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to hEDS, whole exome sequencing was performed on families and a cohort of sporadic hEDS patients. A missense variant in Kallikrein-15 (KLK15 p. Gly226Asp), segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the Kallikrein gene family. To validate...
- Maximizing Insights from Longitudinal Epigenetic Age Data: Simulations, Applications, and Practical Guidanceon July 1, 2024
CONCLUSION: Our results can serve as a guide for forthcoming longitudinal EA studies, aiding in methodological decisions that may determine whether an association is accurately estimated, overestimated, or potentially overlooked.
- Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progressionon July 1, 2024
CONCLUSION: Non- DNMT3A CHIP is a potentially targetable novel risk factor for CKD progression.
- Brain-age prediction: Systematic evaluation of site effects, and sample age range and sizeon July 1, 2024
Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model....
- Distinct genetic liability profiles define clinically relevant patient strata across common diseaseson July 1, 2024
Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the...
- Understanding the genetic complexity of puberty timing across the allele frequency spectrumon July 1, 2024
Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women,...
- Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effectson July 1, 2024
Huntington's disease (HD), due to expansion of a CAG repeat in HTT , is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of...
- Considerations for reporting variants in novel candidate genes identified during clinical genomic testingon June 30, 2024
Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic...
- Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobankon June 29, 2024
The phenotypic impact of compound heterozygous (CH) variation has not been investigated at the population scale. We phased rare variants (MAF ∼0.001%) in the UK Biobank (UKBB) exome-sequencing data to characterize recessive effects in 175,587 individuals across 311 common diseases. A total of 6.5% of individuals carry putatively damaging CH variants, 90% of which are only identifiable upon phasing rare variants (MAF
- Polygenic Background Modifies Risk of Coronary Artery Disease Among Individuals With Heterozygous Familial Hypercholesterolemiaon June 28, 2024
CONCLUSIONS: In 2 cohort studies involving 1,744 individuals with genetically confirmed HeFH - the largest study to date - risk of CAD varied according to polygenic background, in some cases approaching the risk observed in noncarriers.
- The centrosomal protein FGFR1OP controls myosin function in murine intestinal epithelial cellson June 28, 2024
Recent advances in human genetics have shed light on the genetic factors contributing to inflammatory diseases, particularly Crohn's disease (CD), a prominent form of inflammatory bowel disease. Certain risk genes associated with CD directly influence cytokine biology and cell-specific communication networks. Current CD therapies primarily rely on anti-inflammatory drugs, which are inconsistently effective and lack strategies for promoting epithelial restoration and mucosal balance. To...
- Associations between lipoprotein(a), oxidized phospholipids, and extracoronary vascular diseaseon June 28, 2024
The roles of lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPLs) in the development and progression of coronary disease is known, but their influence on extracoronary vascular disease is not well-established. We sought to evaluate associations between Lp(a), OxPL apolipoprotein B (OxPL-apoB), and apolipoprotein(a) (OxPL-apo(a)) with angiographic extracoronary vascular disease and incident major adverse limb events (MALEs). Four hundred forty-six participants who underwent […]
- The role of accelerometer-derived sleep traits on glycated haemoglobin and glucose levels: a Mendelian randomization studyon June 28, 2024
Self-reported shorter/longer sleep duration, insomnia, and evening preference are associated with hyperglycaemia in observational analyses, with similar observations in small studies using accelerometer-derived sleep traits. Mendelian randomization (MR) studies support an effect of self-reported insomnia, but not others, on glycated haemoglobin (HbA1c). To explore potential effects, we used MR methods to assess effects of accelerometer-derived sleep traits (duration, mid-point least active […]
- A blood-brain barrier-penetrant AAV gene therapy improves neurological function in symptomatic mucolipidosis IV miceon June 27, 2024
Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using adeno-associated vector 9 (AAV9) and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the human MCOLN1 gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-oriented MCOLN1 gene expression vector and...
- Sleep and home parenteral nutrition in adults: A narrative reviewon June 27, 2024
Infusions of home parenteral nutrition (HPN) are often cycled at night coinciding with sleep episodes. Adult consumers of HPN are known to experience poor sleep attributed to frequent awakenings and long durations of wakefulness after falling asleep. Consequently, most consumers do not meet recommendations for sleep duration and quality or daytime napping. The primary underlying pathophysiology resulting in sleep problems is nocturia; however, other factors also exist, including disruptions...
- A common flanking variant is associated with enhanced stability of the FGF14-SCA27B repeat locuson June 27, 2024
The factors driving or preventing pathological expansion of tandem repeats remain largely unknown. Here, we assessed the FGF14 (GAA)·(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a common 5'-flanking variant in 70.34% of alleles analyzed (3,463/4,923) that represents the phylogenetically ancestral allele and is present on all major haplotypes. This common sequence variation is present nearly exclusively on nonpathogenic alleles with fewer than 30...
- Programmable RNA-guided enzymes for next-generation genome editingon June 26, 2024
No abstract
- Tailored vs. General COVID-19 prevention for adults with mental disabilities residing in group homes: a randomized controlled effectiveness-implementation trialon June 26, 2024
CONCLUSION: Tailored COVID-19 prevention strategies are beneficial as a feasible and acceptable implementation strategy with the potential to reduce disparities in vaccine acceptance among the subgroup of non-White individuals with mental disabilities.
- Occurrence of mosaic Down syndrome and prevalence of co-occurring conditions in Medicaid enrolled adults, 2016-2019on June 26, 2024
BACKGROUND: Mosaic Down syndrome is a triplication of chromosome 21 in some but not all cells. Little is known about the epidemiology of mosaic Down syndrome. We described prevalence of mosaic Down syndrome and the co-occurrence of common chronic conditions in 94,533 Medicaid enrolled adults with any Down syndrome enrolled from 2016 to 2019.
- Reanalysis of RNA sequencing data ends diagnostic odyssey and expands the phenotypic spectrum of congenital titinopathyon June 26, 2024
Although next-generation sequencing has enabled diagnoses for many patients with Mendelian disorders, the majority remain undiagnosed. Here, we present a sibling pair who were clinically diagnosed with Escobar syndrome, however targeted gene testing was negative. Exome sequencing (ES), and later genome sequencing (GS), revealed compound heterozygous TTN variants in both siblings, a maternally inherited frameshift variant [(NM_133378.4):c.36812del; p.(Asp12271Valfs*10)], and a paternally...
- Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Databaseon June 25, 2024
Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a...
- Genome-wide Polygenic Risk Scores Predict Risk of Glioma and Molecular Subtypeson June 25, 2024
CONCLUSIONS: Genome-wide PRS has potential to enhance the detection of high-risk individuals and help distinguish between prognostic glioma subtypes.
- Adaptive selection at G6PD and disparities in diabetes complicationson June 25, 2024
Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African populations, confers malaria resistance, and reduces hemoglobin A1c (HbA1c) levels by shortening erythrocyte lifespan. In a combined-ancestry genome-wide association study of diabetic retinopathy, we identified nine loci including a G6PDdef causal variant, rs1050828 -T (Val98Met), which was also associated with increased risk of other...
- Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopmenton June 25, 2024
CONCLUSION: These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.
- Deep learning-based prediction of one-year mortality in Finland is an accurate but unfair aging markeron June 24, 2024
Short-term mortality risk, which is indicative of individual frailty, serves as a marker for aging. Previous age clocks focused on predicting either chronological age or longer-term mortality. Aging clocks predicting short-term mortality are lacking and their algorithmic fairness remains unexamined. We developed a deep learning model to predict 1-year mortality using nationwide longitudinal data from the Finnish population (FinRegistry; n = 5.4 million), incorporating more than 8,000 features...
- Feeding critically ill patients at the right time of dayon June 24, 2024
No abstract
- Using simulation modeling to inform intervention and implementation selection in a rapid stakeholder-engaged hybrid effectiveness-implementation randomized trialon June 24, 2024
CONCLUSIONS: Vaccination and decreasing vaccine hesitancy among staff were predicted to have the greatest impact in mitigating COVID-19 risk in vulnerable populations of group home residents and staff. Simulation modeling was effective in rapidly informing the selection of the prevention and implementation strategy in a hybrid effectiveness-implementation trial. Future implementation may benefit from this approach when rapid deployment is necessary in the absence of data on tailored...
- Evaluation of polygenic scoring methods in five biobanks shows larger variation between biobanks than methods and finds benefits of ensemble learningon June 22, 2024
Methods of estimating polygenic scores (PGSs) from genome-wide association studies are increasingly utilized. However, independent method evaluation is lacking, and method comparisons are often limited. Here, we evaluate polygenic scores derived via seven methods in five biobank studies (totaling about 1.2 million participants) across 16 diseases and quantitative traits, building on a reference-standardized framework. We conducted meta-analyses to quantify the effects of method choice,...
- SMIM1 absence is associated with reduced energy expenditure and excess weighton June 21, 2024
CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them.
- Prioritization of Kidney Cell Types Highlights Myofibroblast Cells in Regulating Human Blood Pressureon June 20, 2024
CONCLUSION: Our findings provide a solid basis for follow-up studies to further identify genes and mechanisms in myofibroblast cells that underlie the regulation of BP.
- Plasma metabolomics changes comparing daytime to overnight infusions of home parenteral nutrition in adult patients with short bowel syndrome: Secondary analysis of a clinical trialon June 20, 2024
CONCLUSION: Daytime infusions of HPN may result in changes in circulating lipids and amino acid composing metabolic pathways previously implicated in circadian rhythms. As this is the first untargeted metabolomics study of HPN, larger studies are needed.
- Identification of genetic modifiers of Huntington's disease somatic CAG repeat instability by in vivo CRISPR-Cas9 genome editingon June 19, 2024
Huntington's disease (HD), one of >50 inherited repeat expansion disorders (Depienne and Mandel, 2021), is a dominantly-inherited neurodegenerative disease caused by a CAG expansion in HTT (The Huntington's Disease Collaborative Research Group, 1993). Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the property driving disease is the CAG length-dependent propensity of the repeat to further expand in brain (Swami et al ., […]
- TSC2 loss in neural progenitor cells suppresses translation of ASD/NDD-associated transcripts in an mTORC1- and MNK1/2-reversible fashionon June 19, 2024
Tuberous sclerosis complex (TSC) is an inherited neurodevelopmental disorder (NDD) with frequent manifestations of epilepsy and autism spectrum disorder (ASD). TSC is caused by inactivating mutations in TSC1 or TSC2 tumor suppressor genes, with encoded proteins hamartin (TSC1) and tuberin (TSC2) forming a functional complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. This has led to treatment with allosteric mTORC1 inhibitor rapamycin analogs ("rapalogs") for TSC...
- Variant level heritability estimates of type 2 diabetes in African Americanson June 18, 2024
Type 2 diabetes (T2D) is caused by both genetic and environmental factors and is associated with an increased risk of cardiorenal complications and mortality. Though disproportionately affected by the condition, African Americans (AA) are largely underrepresented in genetic studies of T2D, and few estimates of heritability have been calculated in this race group. Using genome-wide association study (GWAS) data paired with phenotypic data from ~ 19,300 AA participants of the Reasons for...
- A Qualitative Study of Facilitators, Barriers, and Gender Disparities in Academic Neurologyon June 17, 2024
BACKGROUND AND OBJECTIVES: To understand the challenges and facilitators of a successful academic neurology research career broadly and to identify gender-based disparities specifically.
- Clonal Hematopoiesis of Indeterminate Potential and Long-term Outcomes in Heart Transplantationon June 17, 2024
CONCLUSION: We demonstrated no association between CHIP mutations and post-transplant outcomes, including CAV, graft failure, malignancy, and all-cause mortality. In line with previously published data, our analysis provides additional evidence about the lack of clinical value of using CHIP mutations as a biomarker for surveillance in outcomes after HT.
- Deep learning survival model predicts outcome after intracerebral hemorrhage from initial CT scanon June 16, 2024
CONCLUSION: We developed a generalizable deep learning model to predict onset of dependent living and disability after ICH, which could help to guide treatment decisions, advise relatives in the acute setting, optimize rehabilitation strategies, and anticipate long-term care needs.
- Management of subdural haematoma: optimising drainageon June 15, 2024
No abstract
- Predictors of COVID-19 infection and hospitalization in group homes for individuals with intellectual and/or developmental disabilitieson June 15, 2024
CONCLUSIONS: Aggressive efforts to decrease resident density, staff-to-resident ratios, and staff infections through efforts such as vaccination, in addition to ongoing access to personal protective equipment and COVID-19 testing, may reduce COVID-19 and related hospitalizations in people with ID/DD living in group homes.
- Using Sex-Specific Polygenic Risk to Prognosticate Coronary Artery Disease in Womenon June 14, 2024
No abstract
- Phenotypic and ancestry-related assortative mating in autismon June 14, 2024
CONCLUSIONS: This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for
- Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's diseaseon June 13, 2024
An expanded CAG repeat in the huntingtin gene (HTT) 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...
- Contribution of copy number variants on antipsychotic treatment response in Han Chinese patients with schizophreniaon June 13, 2024
BACKGROUND: Response to antipsychotic drugs (APD) varies greatly among individuals and is affected by genetic factors. This study aims to demonstrate genome-wide associations between copy number variants (CNVs) and response to APD in patients with schizophrenia.
- De novo TLK1 and MDM1 mutations in a patient with a neurodevelopmental disorder and immunodeficiencyon June 13, 2024
The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants underlie the neurodevelopmental disorder (NDD) 'Intellectual Disability, Autosomal Dominant 57' (MRD57), characterized by intellectual disability and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency […]
- Clinical outcome assessments of disease burden and progression in late-onset GM2 gangliosidoseson June 13, 2024
The late-onset GM2 gangliosidoses, comprising late-onset Tay-Sachs and Sandhoff diseases, are rare, slowly progressive, neurogenetic disorders primarily characterized by neurogenic weakness, ataxia, and dysarthria. The aim of this longitudinal study was to characterize the natural history of late-onset GM2 gangliosidoses using a number of clinical outcome assessments to measure different aspects of disease burden and progression over time, including neurological, functional, and quality of […]
- Study on Circulating Tumor Cell Detection System Based on Microfluidic Chipon June 12, 2024
CONCLUSION: CTCs detection system can achieve high detection rate and has good reliability, which can provide a reliable reference for clinical research in related fields.
- Dimensional Measures of Psychopathology in Children and Adolescents Using Large Language Modelson June 12, 2024
CONCLUSIONS: An LLM extracted estimates of 6 RDoC domains in an explainable manner, which were associated with clinical outcomes. This approach can contribute to a new generation of prediction models or biological investigations based on dimensional psychopathology.
- TWINGEN: protocol for an observational clinical biobank recall and biomarker cohort study to identify Finnish individuals with high risk of Alzheimer's diseaseon June 12, 2024
INTRODUCTION: A better understanding of the earliest stages of Alzheimer's disease (AD) could expedite the development or administration of treatments. Large population biobanks hold the promise to identify individuals at an elevated risk of AD and related dementias based on health registry information. Here, we establish the protocol for an observational clinical recall and biomarker study called TWINGEN with the aim to identify individuals at high risk of AD by assessing cognition, health […]
- A unified framework for estimating country-specific cumulative incidence for 18 diseases stratified by polygenic riskon June 12, 2024
Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across the life course; a key benefit over short-term prediction models. To produce risk estimates relevant to clinical and public health decision-making, it is important to account for varying effects due to age and sex. Here, we develop a novel framework to estimate country-, age-, and sex-specific estimates of cumulative incidence stratified by PGS for 18 high-burden diseases. We integrate PGS […]
- Genetic drivers and cellular selection of female mosaic X chromosome losson June 12, 2024
Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals^(1,2), but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 […]
- Melatonin decreases human adipose tissue insulin sensitivityon June 11, 2024
Melatonin is a pineal hormone that modulates the circadian system and exerts soporific and phase-shifting effects. It is also involved in many other physiological processes, such as those implicated in cardiovascular, endocrine, immune, and metabolic functions. However, the role of melatonin in glucose metabolism remains contradictory, and its action on human adipose tissue (AT) explants has not been demonstrated. We aimed to assess whether melatonin (a pharmacological dose) influences […]
- Whole-genome sequencing identifies variants in ANK1, LRRN1, HAS1, and other genes and regulatory regions for stroke in type 1 diabeteson June 11, 2024
Individuals with type 1 diabetes (T1D) carry a markedly increased risk of stroke, with distinct clinical and neuroimaging characteristics as compared to those without diabetes. Using whole-exome or whole-genome sequencing of 1,051 individuals with T1D, we aimed to find rare and low-frequency genomic variants associated with stroke in T1D. We analysed the genome comprehensively with single-variant analyses, gene aggregate analyses, and aggregate analyses on genomic windows, enhancers and...
PublicationsCGM Admin2023-08-22T11:44:51-04:00