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

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadHeart 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.Siemens Diagnostics Aegerion Pharmaceuticals Amgen AstraZeneca Danone Research Hoffmann-La Roche MSD Pfizer Sanofi Synageva BASF Abbott Laboratories Numares AG Berlin-Chemie GlaxoSmithKline Eisai Inc Merck & Company AstraZeneca Johnson & Johnson USA Novo Nordisk Bayer AG Bristol-Myers Squibb Pfizer Boehringer Ingelheim Bayer A