Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
Regeneron Genetics Center
(2020) Nature Communications, volume 11, issue 1, pp. 1 - 12
(Article)
Abstract
Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of
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HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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Keywords: Adaptor Proteins, Signal Transducing/genetics, Apoptosis Regulatory Proteins/genetics, Atrial Fibrillation/genetics, Cardiomyopathies/genetics, Carrier Proteins/genetics, Case-Control Studies, Coronary Artery Disease/genetics, Cyclin-Dependent Kinase Inhibitor p21/genetics, Genome-Wide Association Study, Heart Failure/genetics, Humans, Mendelian Randomization Analysis, Microfilament Proteins/genetics, Muscle Proteins/genetics, Risk Factors, Ventricular Function, Left/genetics, General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology, Meta-Analysis, Journal Article
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: J.B.W., L.B., Xing Chen, C.L.H., M.W.N. and A. Malarstig are current or former employee of Pfizer who may hold Pfizer stock and/or stock options. J.D.B. and J.C. are employees of Regeneron Genetics Center. M.E.D. is an employee of Regeneron Pharmaceuticals. W.M. reports grants and personal fees from Siemens Diagnostics, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants and personal fees from Astrazeneca, grants and personal fees from Danone Research, personal fees from Hoffmann LaRoche, personal fees from MSD, grants and personal fees from Pfizer, personal fees from Sanofi, personal fees from Synageva, grants and personal fees from BASF, grants from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, employment with Synlab Holding Deutschland GmbH, all outside the submitted work. M.L.O. reports grant support from GlaxoSmithKline, Eisai, Janssen, Merck and AstraZeneca. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. V.S. participated in a conference trip sponsored by Novo Nordisk and received a honorarium from the same source for participating in an advisory board meeting. He also has ongoing research collaboration with Bayer Ltd. B.T. is a full-time employee of Servier. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG and Boehringer Ingelheim, and has consulted for Abbott, Quest Diagnostics and Bristol Myers Squibb/Pfizer. M.V.H. has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of the The Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment. P.T.E. receives sponsored research support from Bayer AG, and has consulted with Bayer AG, Novartis and Quest Diagnostics. D.I.S. is a full-time employee of Bene-volentAI. R.T.L. has received research grants from Pfizer. The remaining authors declare no competing interest. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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