Trans-ethnic genome-wide association study of severe COVID-19

AbstractCOVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10−10, allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10−9, AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10−8, AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19.

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Role of the LF-SINE–Derived Distal ISL1 Enhancer in Patients with Classic Bladder Exstrophy

Journal of Pediatric Genetics ◽

10.1055/s-0037-1602387 ◽

2017 ◽

Vol 06 (03) ◽

pp. 169-173 ◽

Cited By ~ 1

Author(s):

Rong Zhang ◽

Michael Knapp ◽

Franziska Kause ◽

Heiko Reutter ◽

Michael Ludwig

Keyword(s):

Genome Wide Association Study ◽

Repetitive Element ◽

Meta Analysis ◽

Susceptibility Gene ◽

Bladder Exstrophy ◽

Genome Wide Association ◽

Embryonic Mouse ◽

Genome Wide ◽

A Genome

AbstractA genome-wide association study and meta-analysis identified ISL1 as the first genome-wide significant susceptibility gene for classic bladder exstrophy (CBE). A short interspersed repetitive element (SINE), first detected in lobe-finned fishes (LF-SINE), was shown to drive Isl1 expression in embryonic mouse genital eminence. Hence, we assumed this enhancer a conclusive target for mutations associated with CBE formation and analyzed a cohort of 200 CBE patients. Although we identified two enhancer variants in five CBE patients, their clinical significance seems unlikely, implying that sequence variants in the ISL1 LF-SINE enhancer are not frequently associated with CBE.

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Multi-Ancestry Meta-Analysis yields novel genetic discoveries and ancestry-specific associations

10.1101/2021.04.23.441003 ◽

2021 ◽

Author(s):

Patrick Turley ◽

Alicia R. Martin ◽

Grant Goldman ◽

Hui Li ◽

Masahiro Kanai ◽

...

Keyword(s):

Error Rate ◽

Genome Wide Association Study ◽

Meta Analysis ◽

East Asian ◽

Genome Wide Association ◽

European Ancestry ◽

Summary Statistics ◽

Type 1 Error ◽

Genome Wide

ABSTRACTWe present a new method, Multi-Ancestry Meta-Analysis (MAMA), which combines genome-wide association study (GWAS) summary statistics from multiple populations to produce new summary statistics for each population, identifying novel loci that would not have been discovered in either set of GWAS summary statistics alone. In simulations, MAMA increases power with less bias and generally lower type-1 error rate than other multi-ancestry meta-analysis approaches. We apply MAMA to 23 phenotypes in East-Asian- and European-ancestry populations and find substantial gains in power. In an independent sample, novel genetic discoveries from MAMA replicate strongly.

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International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

Nature Communications ◽

10.1038/s41467-019-12576-w ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 50

Author(s):

Caroline M. Nievergelt ◽

Adam X. Maihofer ◽

Torsten Klengel ◽

Elizabeth G. Atkinson ◽

Chia-Yen Chen ◽

...

Keyword(s):

Genome Wide Association Study ◽

Association Studies ◽

Meta Analysis ◽

African Ancestry ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

Abstract The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

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Genome-wide association study meta-analysis identifies the SOAT1/AXDND1 locus to be associated with hip and forearm fracture risk

Bone Abstracts ◽

10.1530/boneabs.1.pp279 ◽

2013 ◽

Author(s):

Ulrika Pettersson-Kymmer ◽

Andrea Lacroix ◽

Joel Eriksson ◽

Ulrica Bergstrom ◽

Beatrice Melin ◽

...

Keyword(s):

Fracture Risk ◽

Association Study ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Forearm Fracture ◽

Genome Wide Association ◽

Genome Wide

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Faculty Opinions recommendation of Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718310292.793531798 ◽

2017 ◽

Author(s):

Erik Melen

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Association Study ◽

Pulmonary Disease ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Genome Wide ◽

A Genome

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Abstract 16003: Genetic Variation Associated With Favorable Exercise Response in Patients With Systolic Heart Failure: A Hf-action Trial Substudy

Circulation ◽

10.1161/circ.142.suppl_3.16003 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Sara Coles ◽

Stephanie Giamberardino ◽

Carol Haynes ◽

Ruicong She ◽

Hongsheng Gui ◽

...

Keyword(s):

Heart Failure ◽

Clinical Trial ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Systolic Heart Failure ◽

Genome Wide Association ◽

Supervised Exercise ◽

Genome Wide ◽

A Genome ◽

Response To Exercise

Background: Exercise has shown benefit in patients with systolic heart failure, including in the clinical trial Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION). There is heterogeneity in who derives benefit from exercise, and the biologic mechanisms of favorable response to exercise in systolic heart failure are not well understood. Hypothesis: Genetic variation is an underlying factor influencing heterogeneity in response to exercise in patients with systolic heart failure. Methods: The HF-ACTION trial randomized individuals with systolic heart failure (left ventricular ejection fraction <35%) to supervised exercise versus usual care. In this study, we performed a genome wide association study (GWAS) in the HF-ACTION biorepository using the Axiom Biobank1 genotyping array (13,403,591 single nucleotide polymorphisms [SNPs] after quality control on directly genotyped and 1000 genomes imputed data), in N=377 study subjects who completed the supervised exercise arm. Using change in peak VO2 as our outcome, we ran within-ancestry GWASes, modeling SNP effects as both additive and dominant, and conducted across-ancestry meta-analysis within each genetic model. Results: Five loci met genome-wide significance in the European ancestry analyses, 5 loci in the African ancestry, and 8 in the meta-analyses. The two most significantly associated loci across both additive and dominant meta-analysis models were rs111577308 located in the histone acetylation for transcription elongator complex 3 gene ( ELP3, p=1.212x10 -9 ) and rs75444785 located in the phosphodiesterase 4D gene ( PDE4D , p=1.565x10 -9 ). ELP3 is responsible for histone modifications related to DNA transcription factor complexes, and PDE4D is involved in cyclic AMP cell signaling. In silico analysis of these loci showed that they are in linkage with regions associated with skeletal muscle and peripheral vascular disease phenotypes. Conclusions: Using a genome-wide association study in a well-phenotyped clinical trial of exercise in systolic heart failure, we found common genetic variants in genes involved in DNA transcription histone modification and cyclic AMP cell signaling that are associated with a more favorable response to exercise.

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Expanded Genome-Wide Association Study Meta-Analysis of Psoriasis Expands the Catalog of Common Psoriasis-Associated Variants

Journal of Investigative Dermatology Symposium Proceedings ◽

10.1016/j.jisp.2018.09.005 ◽

2018 ◽

Vol 19 (2) ◽

pp. S77-S78 ◽

Cited By ~ 9

Author(s):

James T. Elder

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide

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Heritability and genome-wide association study of diffusing capacity of the lung

10.1101/277343 ◽

2018 ◽

Author(s):

Natalie Terzikhan ◽

Fangui Sun ◽

Fien M. Verhamme ◽

Hieab H.H. Adams ◽

Daan Loth ◽

...

Keyword(s):

Genome Wide Association Study ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Considerable Proportion ◽

Genome Wide Association Studies ◽

Diffusing Capacity ◽

Human Lung Tissue ◽

Alveolar Volume ◽

Genome Wide

AbstractBackgroundAlthough several genome wide association studies (GWAS) have investigated the genetics of pulmonary ventilatory function, little is known about the genetic factors that influence gas exchange.AimTo investigate the heritability of, and genetic variants associated with the diffusing capacity of the lung.MethodsGWAS was performed on diffusing capacity, measured by carbon monoxide uptake (DLCO) and per alveolar volume (DLCO/VA) using the single-breath technique, in 8,372 individuals from two population-based cohort studies, the Rotterdam Study and the Framingham Heart Study. Heritability was estimated in related (n=6,246) and unrelated (n=3,286) individuals.ResultsHeritability of DLCO and DLCO/VA ranged between 23% and 28% in unrelated individuals and between 45% and 49% in related individuals. Meta-analysis identified a genetic variant in GPR126 that is significantly associated with DLCO/VA. Gene expression analysis of GPR126 in human lung tissue revealed a decreased expression in patients with COPD and subjects with decreased DLCO/VA.ConclusionDLCO and DLCO/VA are heritable traits, with a considerable proportion of variance explained by genetics. A functional variant in GPR126 gene region was significantly associated with DLCO/VA. Pulmonary GPR126 expression was decreased in patients with COPD.

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Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003148 ◽

2021 ◽

Author(s):

Mengyao Yu ◽

Sergiy Kyryachenko ◽

Stephanie Debette ◽

Philippe Amouyel ◽

Jean-Jacques Schott ◽

...

Keyword(s):

Mitral Valve ◽

Association Study ◽

Genome Wide Association Study ◽

Cardiac Development ◽

Meta Analysis ◽

Genome Wide Association ◽

Uk Biobank ◽

Additional Risk ◽

Genome Wide ◽

The Uk

Background: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study have identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank. Methods: We reanalyzed 1007/479 cases from the MVP-France study, 1469/862 controls from the MVP-Nantes study for reimputation genotypes using HRC and TOPMed panels. We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used FUMA for post-genome-wide association study annotations and MAGMA for gene-based and gene-set analyses. Results: We found TOPMed imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near TNS1 . We identified an additional risk locus on Chr1 ( SYT2 ) and 2 suggestive risk loci on chr8 ( MSRA ) and chr19 ( FBXO46 ), all driven by common variants. Gene-based association using MAGMA revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development. Conclusions: We report an updated meta-analysis genome-wide association study for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.

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