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

Regeneron Genetics Center

Research output: Contribution to journalArticlepeer-review

396 Scopus citations

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.

Original languageEnglish (US)
Article number163
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Jan 9 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

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

PubMed: MeSH publication types

  • Meta-Analysis
  • Journal Article

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