Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure
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Published:2022-11-14
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Levin Michael G.ORCID, Tsao Noah L.ORCID, Singhal Pankhuri, Liu ChangORCID, Vy Ha My T., Paranjpe Ishan, Backman Joshua D.ORCID, Bellomo Tiffany R., Bone William P., Biddinger Kiran J., Hui QinORCID, Dikilitas OzanORCID, Satterfield Benjamin A.ORCID, Yang Yifan, Morley Michael P., Bradford Yuki, Burke MeganORCID, Reza Nosheen, Charest Brian, Judy Renae L., Puckelwartz Megan J.ORCID, Hakonarson Hakon, Khan AtlasORCID, Kottyan Leah C.ORCID, Kullo IftikharORCID, Luo YuanORCID, McNally Elizabeth M., Rasmussen-Torvik Laura J., Day Sharlene M., Do RonORCID, Phillips Lawrence S., Ellinor Patrick T.ORCID, Nadkarni Girish N.ORCID, Ritchie Marylyn D.ORCID, Arany ZoltanORCID, Cappola Thomas P., Margulies Kenneth B., Aragam Krishna G.ORCID, Haggerty Christopher M.ORCID, Joseph Jacob, Sun Yan V.ORCID, Voight Benjamin F.ORCID, Damrauer Scott M.ORCID,
Abstract
AbstractHeart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets.
Funder
U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences U.S. Department of Health & Human Services | National Institutes of Health American Heart Association Fondation Leducq U.S. Department of Veterans Affairs U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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