2023
Benson, Mark D | Eisman, Aaron S | Tahir, Usman A | Katz, Daniel H | Deng, Shuliang | Ngo, Debby | Robbins, Jeremy M | Hofmann, Alissa | Shi, Xu | Zheng, Shuning | Keyes, Michelle | Yu, Zhi | Gao, Yan | Farrell, Laurie | Shen, Dongxiao | Chen, Zsu-Zsu | Cruz, Daniel E | Sims, Mario | Correa, Adolfo | Tracy, Russell P | Durda, Peter | Taylor, Kent D | Liu, Yongmei | Johnson, W Craig | Guo, Xiuqing | Yao, Jie | Chen, Yii-Der Ida | Manichaikul, Ani W | Jain, Deepti | Yang, Qiong | | Bouchard, Claude | Sarzynski, Mark A | Rich, Stephen S | Rotter, Jerome I | Wang, Thomas J | Wilson, James G | Clish, Clary B | Sarkar, Indra Neil | Natarajan, Pradeep | Gerszten, Robert E
Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma Journal Article
In: Cell Metab, vol. 35, no. 9, pp. 1646–1660.e3, 2023, ISSN: 1932-7420.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Szczerbinski, Lukasz | Mandla, Ravi | Schroeder, Philip | Porneala, Bianca C | Li, Josephine H | Florez, Jose C | Mercader, Josep M | Manning, Alisa K | Udler, Miriam S
2023.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Shellock, Frank G | Rosen, Matthew S | Webb, Andrew | Kimberly, W Taylor | Rajan, Sunder | Nacev, Aleksandar N | Crues, John V
Managing Patients With Unlabeled Passive Implants on MR Systems Operating Below 1.5 T Journal Article
In: J Magn Reson Imaging, 2023, ISSN: 1522-2586.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
van Essen, Thomas A | van Erp, Inge A M | Lingsma, Hester F | Pisică, Dana | Yue, John K | Singh, Ranjit D | van Dijck, Jeroen T J M | Volovici, Victor | Younsi, Alexander | Kolias, Angelos | Peppel, Lianne D | Heijenbrok-Kal, Majanka | Ribbers, Gerard M | Menon, David K | Hutchinson, Peter J A | Manley, Geoffrey T | Depreitere, Bart | Steyerberg, Ewout W | Maas, Andrew I R | de Ruiter, Godard C W | and, Wilco C Peul
In: EClinicalMedicine, vol. 63, pp. 102161, 2023, ISSN: 2589-5370.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Nowbandegani, Pouria Salehi | Wohns, Anthony Wilder | Ballard, Jenna L | Lander, Eric S | Bloemendal, Alex | Neale, Benjamin M | O'Connor, Luke J
Extremely sparse models of linkage disequilibrium in ancestrally diverse association studies Journal Article
In: Nat Genet, vol. 55, no. 9, pp. 1494–1502, 2023, ISSN: 1546-1718.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Kitano, Rie | Madan, Neel | Mikami, Takahisa | Madankumar, Rajeevi | Skotko, Brian G | Santoro, Stephanie | Ralston, Steven J | Bianchi, Diana W | Tarui, Tomo
Biometric magnetic resonance imaging analysis of fetal brain development in down syndrome Journal Article
In: Prenat Diagn, 2023, ISSN: 1097-0223.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Kathiresan, Nina | Cho, So Mi Jemma | Bhattacharya, Romit | Truong, Buu | Hornsby, Whitney | Natarajan, Pradeep
Representation of Race and Ethnicity in the Contemporary US Health Cohort All of Us Research Program Journal Article
In: JAMA Cardiol, vol. 8, no. 9, pp. 859–864, 2023, ISSN: 2380-6591.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Cho, So Mi Jemma | Koyama, Satoshi | Honigberg, Michael C | Surakka, Ida | Haidermota, Sara | Ganesh, Shriienidhie | Patel, Aniruddh P | Bhattacharya, Romit | Lee, Hokyou | Kim, Hyeon Chang | Natarajan, Pradeep
Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study Journal Article
In: Eur Heart J, vol. 44, no. 36, pp. 3456–3465, 2023, ISSN: 1522-9645.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Babadi, Mehrtash | Fu, Jack M | Lee, Samuel K | Smirnov, Andrey N | Gauthier, Laura D | Walker, Mark | Benjamin, David I | Zhao, Xuefang | Karczewski, Konrad J | Wong, Isaac | Collins, Ryan L | Sanchis-Juan, Alba | Brand, Harrison | Banks, Eric | Talkowski, Michael E
GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data Journal Article
In: Nat Genet, vol. 55, no. 9, pp. 1589–1597, 2023, ISSN: 1546-1718.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Williams, Camille M | Peyre, Hugo | Wolfram, Tobias | Lee, Younga H | Ge, Tian | Smoller, Jordan W | Mallard, Travis T | Ramus, Franck
Characterizing the phenotypic and genetic structure of psychopathology in UK Biobank Miscellaneous
2023.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Gao, Han | Liu, Ruize | Huang, Hailiang | Liu, Zhanju
Susceptibility gene profiling elucidates the pathogenesis of inflammatory bowel disease and provides precision medicine Journal Article
In: Clin Transl Med, vol. 13, no. 9, pp. e1404, 2023, ISSN: 2001-1326.
@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}
}
Bruffaerts, Ronny | Axinn, William G | Ghimire, Dirgha J | Benjet, Corina | Chardoul, Stephanie | Scott, Kate M | Kessler, Ronald C | Schulz, Paul | Smoller, Jordan W
Community exposure to armed conflict and subsequent onset of alcohol use disorder Journal Article
In: Addiction, 2023, ISSN: 1360-0443.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Uddin, Md Mesbah | Saadatagah, Seyedmohammad | Niroula, Abhishek | Yu, Bing | Hornsby, Whitney | Ganesh, Shriienidhie | Lannery, Kim | Shuermans, Art | Honigberg, Michael C | Bick, Alexander G | Libby, Peter | Ebert, Benjamin L | Ballantyne, Christie M | Natarajan, Pradeep
Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis Miscellaneous
2023.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Lagou, Vasiliki | Jiang, Longda | Ulrich, Anna | Zudina, Liudmila | González, Karla Sofia Gutiérrez | Balkhiyarova, Zhanna | Faggian, Alessia | Maina, Jared G | Chen, Shiqian | Todorov, Petar V | Sharapov, Sodbo | David, Alessia | Marullo, Letizia | Mägi, Reedik | Rujan, Roxana-Maria | Ahlqvist, Emma | Thorleifsson, Gudmar | Gao, Ηe | Εvangelou, Εvangelos | Benyamin, Beben | Scott, Robert A | Isaacs, Aaron | Zhao, Jing Hua | Willems, Sara M | Johnson, Toby | Gieger, Christian | Grallert, Harald | Meisinger, Christa | Müller-Nurasyid, Martina | Strawbridge, Rona J | Goel, Anuj | Rybin, Denis | Albrecht, Eva | Jackson, Anne U | Stringham, Heather M | Corrêa, Ivan R | Farber-Eger, Eric | Steinthorsdottir, Valgerdur | Uitterlinden, André G | Munroe, Patricia B | Brown, Morris J | Schmidberger, Julian | Holmen, Oddgeir | Thorand, Barbara | Hveem, Kristian | Wilsgaard, Tom | Mohlke, Karen L | Wang, Zhe | | Shmeliov, Aleksey | den Hoed, Marcel | Loos, Ruth J F | Kratzer, Wolfgang | Haenle, Mark | Koenig, Wolfgang | Boehm, Bernhard O | Tan, Tricia M | Tomas, Alejandra | Salem, Victoria | Barroso, Inês | Tuomilehto, Jaakko | Boehnke, Michael | Florez, Jose C | Hamsten, Anders | Watkins, Hugh | Njølstad, Inger | Wichmann, H-Erich | Caulfield, Mark J | Khaw, Kay-Tee | van Duijn, Cornelia M | Hofman, Albert | Wareham, Nicholas J | Langenberg, Claudia | Whitfield, John B | Martin, Nicholas G | Montgomery, Grant | Scapoli, Chiara | Tzoulaki, Ioanna | Elliott, Paul | Thorsteinsdottir, Unnur | Stefansson, Kari | Brittain, Evan L | McCarthy, Mark I | Froguel, Philippe | Sexton, Patrick M | Wootten, Denise | Groop, Leif | Dupuis, Josée | Meigs, James B | Deganutti, Giuseppe | Demirkan, Ayse | Pers, Tune H | Reynolds, Christopher A | Aulchenko, Yurii S | Kaakinen, Marika A | Jones, Ben | and, Inga Prokopenko
GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification Journal Article
In: Nat Genet, vol. 55, no. 9, pp. 1448–1461, 2023, ISSN: 1546-1718.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Kipkemoi, Patricia | Kim, Heesu Ally | Christ, Bjorn | O'Heir, Emily | Allen, Jake | Austin-Tse, Christina | Baxter, Samantha | Brand, Harrison | Bryant, Sam | Buser, Nick | de Menil, Victoria | Eastman, Emma | Murugasen, Serini | Galvin, Alice | Kombe, Martha | Ngombo, Alfred | Mkubwa, Beatrice | Mwangi, Paul | Kipkoech, Collins | Lovgren, Alysia | MacArthur, Daniel G | Melly, Brigitte | Mwangasha, Katini | Martin, Alicia | Nkambule, Lethukuthula L | Sanchis-Juan, Alba | Singer-Berk, Moriel | Talkowski, Michael E | VanNoy, Grace | van der Merwe, Celia | | Newton, Charles | O'Donnell-Luria, Anne | Abubakar, Amina | Donald, Kirsten A | Robinson, Elise B
Phenotype and genetic analysis of data collected within the first year of NeuroDev Journal Article
In: Neuron, vol. 111, no. 18, pp. 2800–2810.e5, 2023, ISSN: 1097-4199.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Scammell, B H | Tchio, C | Song, Y | Nishiyama, T | Louie, T L | Dashti, H S | Nakatochi, M | Zee, P C | Daghlas, I | Momozawa, Y | Cai, J | Ollila, H M | Redline, S | Wakai, K | Sofer, T | Suzuki, S | Lane, J M | Saxena, R
Multi-ancestry genome-wide analysis identifies shared genetic effects and common genetic variants for self-reported sleep duration Journal Article
In: Hum Mol Genet, vol. 32, no. 18, pp. 2797–2807, 2023, ISSN: 1460-2083.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Kerimov, Nurlan | Tambets, Ralf | Hayhurst, James D | Rahu, Ida | Kolberg, Peep | Raudvere, Uku | Kuzmin, Ivan | Chowdhary, Anshika | Vija, Andreas | Teras, Hans J | Kanai, Masahiro | Ulirsch, Jacob | Ryten, Mina | Hardy, John | Guelfi, Sebastian | Trabzuni, Daniah | Kim-Hellmuth, Sarah | Rayner, William | Finucane, Hilary | Peterson, Hedi | Mosaku, Abayomi | Parkinson, Helen | Alasoo, Kaur
eQTL Catalogue 2023: New datasets, X chromosome QTLs, and improved detection and visualisation of transcript-level QTLs Journal Article
In: PLoS Genet, vol. 19, no. 9, pp. e1010932, 2023, ISSN: 1553-7404.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Harisinghani, Ayesha | Dhand, Amar | Steffensen, Ellen Hollands | Skotko, Brian G
Sustainability of personal social networks of people with Down syndrome Journal Article
In: Am J Med Genet C Semin Med Genet, pp. e32064, 2023, ISSN: 1552-4876.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Recto, Kathryn | Kachroo, Priyadarshini | Huan, Tianxiao | Berg, David Van Den | Lee, Gha Young | Bui, Helena | Lee, Dong Heon | Gereige, Jessica | Yao, Chen | Hwang, Shih-Jen | Joehanes, Roby | Weiss, Scott T | | O'Connor, George T | Levy, Daniel | DeMeo, Dawn L
Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma Journal Article
In: EBioMedicine, vol. 95, pp. 104758, 2023, ISSN: 2352-3964.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Kim, Min Seo | Song, Minku | Kim, Beomsu | Shim, Injeong | Kim, Dan Say | Natarajan, Pradeep | Do, Ron | Won, Hong-Hee
Prioritization of therapeutic targets for dyslipidemia using integrative multi-omics and multi-trait analysis Journal Article
In: Cell Rep Med, vol. 4, no. 9, pp. 101112, 2023, ISSN: 2666-3791.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Lawson, Jonathan | Ghanaim, Elena M | Baek, Jinyoung | Lee, Harin | Rehm, Heidi L
Aligning NIH's existing data use restrictions to the GA4GH DUO standard Journal Article
In: Cell Genom, vol. 3, no. 9, pp. 100381, 2023, ISSN: 2666-979X.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Joshi, Pallavi R | Sadre, Shayan | Guo, Xiaoyan A | McCoy, Jason G | Mootha, Vamsi K
Lipoylation is dependent on the ferredoxin FDX1 and dispensable under hypoxia in human cells Journal Article
In: J Biol Chem, vol. 299, no. 9, pp. 105075, 2023, ISSN: 1083-351X.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Alghamdi, Malak Ali | O'Donnell-Luria, Anne | Almontashiri, Naif A | AlAali, Wajeih Y | Ali, Hebatallah H | Levy, Harvey L
Classical phenylketonuria presenting as maternal PKU syndrome in the offspring of an intellectually normal woman Miscellaneous
2023, ISSN: 2192-8304.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Vuori, Matti A | Kiiskinen, Tuomo | Pitkänen, Niina | Kurki, Samu | Laivuori, Hannele | Laitinen, Tarja | Mäntylahti, Sampo | Palotie, Aarno | FinnGen, | Niiranen, Teemu J
Use of electronic health record data mining for heart failure subtyping Journal Article
In: BMC Res Notes, vol. 16, no. 1, pp. 208, 2023, ISSN: 1756-0500.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Yu, Zhi | Fidler, Trevor P | Ruan, Yunfeng | Vlasschaert, Caitlyn | Nakao, Tetsushi | Uddin, Md Mesbah | Mack, Taralynn | Niroula, Abhishek | Heimlich, J Brett | Zekavat, Seyedeh M | Gibson, Christopher J | Griffin, Gabriel K | Wang, Yuxuan | Peloso, Gina M | Heard-Costa, Nancy | Levy, Daniel | Vasan, Ramachandran S | Aguet, François | Ardlie, Kristin G | Taylor, Kent D | Rich, Stephen S | Rotter, Jerome I | Libby, Peter | Jaiswal, Siddhartha | Ebert, Benjamin L | Bick, Alexander G | Tall, Alan R | Natarajan, Pradeep
Genetic modification of inflammation- and clonal hematopoiesis-associated cardiovascular risk Journal Article
In: J Clin Invest, vol. 133, no. 18, 2023, ISSN: 1558-8238.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture Journal Article
In: Nat Genet, vol. 55, no. 9, pp. 1471–1482, 2023, ISSN: 1546-1718.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Shashi, Vandana | Schoch, Kelly | Ganetzky, Rebecca | Kranz, Peter G | Sondheimer, Neal | Markert, M Louise | Cope, Heidi | Sadeghpour, Azita | Roehrs, Philip | Arbogast, Thomas | Muraresku, Colleen | | Tyndall, Amanda V | Esser, Michael J | Woodward, Kristine E | Au, Billie Ping-Yee | Parboosingh, Jillian S | Lamont, Ryan E | Bernier, Francois P | Wright, Nicola A M | Benseler, Susa M | Parsons, Simon J | El-Dairi, Mays | Smith, Edward C | Valdez, Purnima | Tennison, Michael | Innes, A Micheil | Davis, Erica E
In: Genet Med, vol. 25, no. 9, pp. 100897, 2023, ISSN: 1530-0366.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Toikumo, Sylvanus | Jennings, Mariela V | Pham, Benjamin K | Lee, Hyunjoon | Mallard, Travis T | Bianchi, Sevim B | Meredith, John J | Vilar-Ribó, Laura | Xu, Heng | Hatoum, Alexander S | Johnson, Emma C | Pazdernik, Vanessa | Jinwala, Zeal | Pakala, Shreya R | Leger, Brittany S | Niarchou, Maria | Ehinmowo, Michael | | | Jenkins, Greg D | Batzler, Anthony | Pendegraft, Richard | Palmer, Abraham A | Zhou, Hang | Biernacka, Joanna M | Coombes, Brandon J | Gelernter, Joel | Xu, Ke | Hancock, Dana B | Nancy, Cox J | Smoller, Jordan W | Davis, Lea K | Justice, Amy C | Kranzler, Henry R | Kember, Rachel L | Sanchez-Roige, Sandra
2023.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Weinhofer, Isabelle | Rommer, Paulus | Gleiss, Andreas | Ponleitner, Markus | Zierfuss, Bettina | Waidhofer-Söllner, Petra | Fourcade, Stéphane | Grabmeier-Pfistershammer, Katharina | Reinert, Marie-Christine | Göpfert, Jens | Heine, Anne | Yska, Hemmo A F | Casasnovas, Carlos | Cantarín, Verónica | Bergner, Caroline G | Mallack, Eric | Forss-Petter, Sonja | Aubourg, Patrick | Bley, Annette | Engelen, Marc | Eichler, Florian | Lund, Troy C | Pujol, Aurora | Köhler, Wolfgang | Kühl, Jörn-Sven | Berger, Johannes
Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy Journal Article
In: EBioMedicine, vol. 96, pp. 104781, 2023, ISSN: 2352-3964.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Hu, Jianhong | Korchina, Viktoriya | Zouk, Hana | Harden, Maegan V | Murdock, David | Macbeth, Alyssa | Harrison, Steven M | Lennon, Niall | Kovar, Christie | Balasubramanian, Adithya | Zhang, Lan | Chandanavelli, Gauthami | Pasham, Divya | Rowley, Robb | Wiley, Ken | Smith, Maureen E | Gordon, Adam | Jarvik, Gail P | Sleiman, Patrick | Kelly, Melissa A | Bland, Harris T | Murugan, Mullai | Venner, Eric | Boerwinkle, Eric | Prows, Cynthia | Mahanta, Lisa | Rehm, Heidi L | Gibbs, Richard A | Muzny, Donna M
Genetic Sex Validation for Sample Tracking in Clinical Testing Miscellaneous
2023.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Larriba, Yolanda | Mason, Ivy C | Saxena, Richa | Scheer, Frank A J L | Rueda, Cristina
In: PLoS Comput Biol, vol. 19, no. 9, pp. e1011510, 2023, ISSN: 1553-7358.
Abstract | Links | BibTeX | Tags:
@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}
}
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/.
Schuermans, Art | Ardissino, Maddalena | Nauffal, Victor | Khurshid, Shaan | Pirruccello, James P | Ellinor, Patrick T | Lewandowski, Adam J | Natarajan, Pradeep | Honigberg, Michael C
Genetically Predicted Gestational Age and Birth Weight Are Associated With Cardiac and Pulmonary Vascular Remodeling in Adulthood Journal Article
In: Eur J Prev Cardiol, 2023, ISSN: 2047-4881.
@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}
}
Zeldovich, Marina | Bockhop, Fabian | Covic, Amra | Mueller, Isabelle | Polinder, Suzanne | Mikolic, Ana | van der Vlegel, Marjolein | von Steinbuechel and, Nicole
In: J Patient Rep Outcomes, vol. 7, no. 1, pp. 90, 2023, ISSN: 2509-8020.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Windred, Daniel P | Burns, Angus C | Lane, Jacqueline M | Saxena, Richa | Rutter, Martin K | Cain, Sean W | Phillips, Andrew J K
Sleep regularity is a stronger predictor of mortality risk than sleep duration: A prospective cohort study Journal Article
In: Sleep, 2023, ISSN: 1550-9109.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Manning, Alisa | Sevilla-González, Magdalena | Smith, Kirk | Wang, Ningyuan | Jensen, Aubrey | Litkowski, Elizabeth | Kim, Hyunkyung | DiCorpo, Daniel | Westerman, Kenneth | Cui, Jinrui | Liu, Ching-Ti | Yu, Chenglong | McNeil, John | Lacaze, Paul | Chang, Kyong-Mi | Tsao, Phil | Phillips, Lawrence | Goodarzi, Mark | Sladek, Rob | Rotter, Jerome | Dupuis, Josee | Florez, Jose | Merino, Jordi | Meigs, James | Zhou, Jin | Raghavan, Sridharan | Udler, Miriam
2023.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Lizano, Paulo | Pong, Sovannarath | Santarriaga, Stephanie | Bannai, Deepthi | Karmacharya, Rakesh
Brain microvascular endothelial cells and blood-brain barrier dysfunction in psychotic disorders Journal Article
In: Mol Psychiatry, 2023, ISSN: 1476-5578.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Wei, Angela | Border, Richard | Fu, Boyang | Cullina, Sinéad | Brandes, Nadav | Sankararaman, Sriram | Kenny, Eimear E | Udler, Miriam S | Ntranos, Vasilis | Zaitlen, Noah | Arboleda, Valerie A
The genetic underpinnings of variable penetrance and expressivity of pathogenic mutations in cardiometabolic traits Miscellaneous
2023.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Maloney, Kristin A | Mizerik, Elizabeth | King, Robin H | McGinnis, Erin M | Perkowitz, Susan | Diamonstein, Callie J | Schmanski, Andrew A | Saliganan, Sheila | Shipper, Andrea G | Udler, Miriam S | Guan, Yue | Pollin, Toni I
Genetic counseling in diabetes mellitus: A practice resource of the National Society of Genetic Counselors Journal Article
In: J Genet Couns, 2023, ISSN: 1573-3599.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Murphy, Michael | Wang, Jun | Jiang, Chenguang | Wang, Lei A | Kozhemiako, Nataliia | Wang, Yining | | Pan, Jen Q | Purcell, Shaun M
A Potential Source of Bias in Group-Level EEG Microstate Analysis Journal Article
In: Brain Topogr, 2023, ISSN: 1573-6792.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Jordan, Elizabeth | Kinnamon, Daniel D | Haas, Garrie J | Hofmeyer, Mark | Kransdorf, Evan | Ewald, Gregory A | Morris, Alanna A | Owens, Anjali | Lowes, Brian | Stoller, Douglas | Tang, W H Wilson | Garg, Sonia | Trachtenberg, Barry H | Shah, Palak | Pamboukian, Salpy V | Sweitzer, Nancy K | Wheeler, Matthew T | Wilcox, Jane E | Katz, Stuart | Pan, Stephen | Jimenez, Javier | Fishbein, Daniel P | Smart, Frank | Wang, Jessica | Gottlieb, Stephen S | Judge, Daniel P | Moore, Charles K | Mead, Jonathan O | Hurst, Natalie | Cao, Jinwen | Huggins, Gordon S | Cowan, Jason | Ni, Hanyu | Rehm, Heidi L | Jarvik, Gail P | Vatta, Matteo | Burke, Wylie | and, Ray E Hershberger
Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry Journal Article
In: JAMA, vol. 330, no. 5, pp. 432–441, 2023, ISSN: 1538-3598.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Feigin, Valery L | Krishnamurthi, Rita | Medvedev, Oleg | Merkin, Alexander | Nair, Balakrishnan | Kravchenko, Michael | Jalili-Moghaddam, Shabnam | Barker-Collo, Suzanne | Ratnasabapathy, Yogini | Skinner, Luke | Owolabi, Mayowa | Norrving, Bo | Sachdev, Perminder S | Arroll, Bruce | Brainin, Michael | Thrift, Amanda | and, Graeme J Hankey
Usability and feasibility of PreventS-MD web app for stroke prevention Journal Article
In: Int J Stroke, pp. 17474930231190745, 2023, ISSN: 1747-4949.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Zhang, Wenqiang | Zhang, Li | Yang, Luo | Xiao, Chenghan | Wu, Xueyao | Yan, Peijing | Cui, Huijie | Yang, Chao | Zhu, Jingwei | Wu, Xuan | Tang, Mingshuang | Wang, Yutong | Chen, Lin | Liu, Yunjie | Zou, Yanqiu | Zhang, Ling | Yang, Chunxia | Yao, Yuqin | Li, Jiayuan | Liu, Zhenmi | Zhang, Ben | and, Xia Jiang
Migraine, chronic kidney disease and kidney function: observational and genetic analyses Journal Article
In: Hum Genet, vol. 142, no. 8, pp. 1185–1200, 2023, ISSN: 1432-1203.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Valencia, Alfredo M | Sankar, Akshay | van der Sluijs, Pleuntje J | Satterstrom, F Kyle | Fu, Jack | Talkowski, Michael E | Vergano, Samantha A Schrier | Santen, Gijs W E | Kadoch, Cigall
Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders Journal Article
In: Nat Genet, vol. 55, no. 8, pp. 1400–1412, 2023, ISSN: 1546-1718.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Hicks, Emily M | Niarchou, Maria | Goleva, Slavina | Kabir, Dia | Ciarcia, Julia | | Smoller, Jordan W | Davis, Lea K | Nievergelt, Caroline M | Koenen, Karestan C | Huckins, Laura M | Choi, Karmel W
Comorbidity Profiles of Posttraumatic Stress Disorder Across the Medical Phenome Miscellaneous
2023.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Marini, Sandro | Chung, Jaeyoon | Han, Xudong | Sun, Xinyu | Parodi, Livia | Farrer, Lindsay A | Rosand, Jonathan | Romero, Jose Rafael | Anderson, Christopher D
Pleiotropy analysis between lobar intracerebral hemorrhage and CSF β-amyloid highlights new and established associations Journal Article
In: Int J Stroke, vol. 18, no. 7, pp. 804–811, 2023, ISSN: 1747-4949.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Morotti, Andrea | Boulouis, Gregoire | Nawabi, Jawed | Li, Qi | Charidimou, Andreas | Pasi, Marco | Schlunk, Frieder | Shoamanesh, Ashkan | Katsanos, Aristeidis H | Mazzacane, Federico | Busto, Giorgio | Arba, Francesco | Brancaleoni, Laura | Giacomozzi, Sebastiano | Simonetti, Luigi | Warren, Andrew D | Laudisi, Michele | Cavallini, Anna | Gurol, Edip | Viswanathan, Anand | Zini, Andrea | Casetta, Ilaria | Fainardi, Enrico | Greenberg, Steven M | Padovani, Alessandro | Rosand, Jonathan | Goldstein, Joshua
Association Between Hematoma Expansion Severity and Outcome and Its Interaction With Baseline Intracerebral Hemorrhage Volume Journal Article
In: Neurology, 2023, ISSN: 1526-632X.
Abstract | Links | BibTeX | Tags:
@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}
}
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.==========.
Maury, Eduardo A | Sherman, Maxwell A | Genovese, Giulio | Gilgenast, Thomas G | Kamath, Tushar | Burris, S J | Rajarajan, Prashanth | Flaherty, Erin | Akbarian, Schahram | Chess, Andrew | McCarroll, Steven A | Loh, Po-Ru | Phillips-Cremins, Jennifer E | Brennand, Kristen J | Macosko, Evan Z | Walters, James T R | O'Donovan, Michael | Sullivan, Patrick | | | Sebat, Jonathan | Lee, Eunjung A | Walsh, Christopher A
Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent and disruptions Journal Article
In: Cell Genom, vol. 3, no. 8, pp. 100356, 2023, ISSN: 2666-979X.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Peters, Cole W | Hanlon, Killian S | Ivanchenko, Maryna V | Zinn, Eric | Linarte, Elizabeth F | Li, Yaqiao | Levy, Jonathan M | Liu, David R | Kleinstiver, Benjamin P | Indzhykulian, Artur A | Corey, David P
Rescue of hearing by adenine base editing in a humanized mouse model of Usher syndrome type 1F Journal Article
In: Mol Ther, vol. 31, no. 8, pp. 2439–2453, 2023, ISSN: 1525-0024.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Kijpaisalratana, Naruchorn | Ament, Zsuzsanna | Patki, Amit | Bhave, Varun M | Jones, Alana C | Guarniz, Ana-Lucia Garcia | Couch, Catharine A | Cushman, Mary | Long, D Leann | Irvin, M Ryan | Kimberly, W Taylor
Acetylglutamine Differentially Associated with First-Time Versus Recurrent Stroke Journal Article
In: Transl Stroke Res, 2023, ISSN: 1868-601X.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
Liu, Fang | Liang, Chen | Li, Zhengchang | Zhao, Sen | Yuan, Haiming | Yao, Ruen | Qin, Zailong | Shangguan, Shaofang | Zhang, Shujie | Zou, Li-Ping | Chen, Qian | Gao, Zhijie | Wen, Suiwen | Peng, Jing | Yin, Fei | Chen, Fei | Qiu, Xiaoxia | Luo, Jingsi | Xie, Yingjun | Lu, Dian | Zhang, Yu | Xie, Hua | Li, Guozhuang | Zhang, Terry Jianguo | Luan, Pengfei | Wang, Hongying | Cui, Xiaodai | Huang, Hailiang | Liu, Ruize | Sun, Xiaofang | Chen, Chao | Wu, Nan | Wang, Jian | Liu, Chunyu | Shen, Yiping | Gusella, James F | Chen, Xiaoli
Haplotype-specific MAPK3 expression in 16p11.2 deletion contributes to variable neurodevelopment Journal Article
In: Brain, vol. 146, no. 8, pp. 3347–3363, 2023, ISSN: 1460-2156.
Abstract | Links | BibTeX | Tags:
@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}
}
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.
The Center for Genomic Medicine (CGM) comprises one of the largest and most vibrant hubs of genomic medicine research in the world. The CGM includes 46 faculty collaborating to define the ‘genomic medicine cycle’ – which envisages a genomics community seeking to advance research from basic genomics research to ultimately using genome information for diagnostics and targeted therapeutics. All of our investigators are faculty at Harvard Medical School, and many members of our community are also investigators at the Broad Institute of Harvard and MIT.
