Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

• Type of Material: Article
• Authors: Sonia Shah, University of Queensland; Albert Henry, University College London; Carolina Roselli, Broad Institute of MIT and Harvard; Honghuang Lin, Boston University; Gardar Sveinbjornsson, Amgen Inc; Ghazaleh Fatemifar, University College London; Asa K. Hedman, Karolinska Institutet; Jemma B. Wilk, Pfizer Worldwide Research and Development; Michael P. Morley, University of Pennsylvania; Mark D. Chaffin, Broad Institute of MIT and Harvard; Anna Helgadottir, Amgen Inc; Niek Verweij, Broad Institute of MIT and Harvard; Abbas Dehghan, Imperial College London; Heather Bloom, Emory University
• Language: English
• Date: 2020-01-09
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2020, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-019-13690-5
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 163
• End Page: 163
• Keywords: Science & Technology; IMPUTATION; RISK; CATALOG; Science & Technology - Other Topics; RESOURCE; HYPERTENSION; Multidisciplinary Sciences; DISEASE; EPIDEMIOLOGY; METAANALYSIS; OBESITY; LOCI
• Research Categories: Biology, Genetics; Health Sciences, Epidemiology

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 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.