Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure

Abstract
Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. 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 unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.
Footnotes
Competing interests 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, 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 BenevolentAI. R.T.L. has received research grants from Pfizer. The remaining authors declare no competing interest.
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