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

TitleGenome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.
Publication TypeJournal Article
Year of Publication2020
AuthorsShah S, Henry A, Roselli C, et al.
Secondary AuthorsR Lumbers T
Corporate AuthorsRegeneron Genetics Center
JournalNat Commun
Volume11
Issue1
Pagination163
Date Published2020 01 09
ISSN2041-1723
KeywordsAdaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, Atrial Fibrillation, Cardiomyopathies, Carrier Proteins, Case-Control Studies, Coronary Artery Disease, Cyclin-Dependent Kinase Inhibitor p21, Genome-Wide Association Study, Heart Failure, Humans, Mendelian Randomization Analysis, Microfilament Proteins, Muscle Proteins, Risk Factors, Ventricular Function, Left
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.

DOI10.1038/s41467-019-13690-5
Alternate JournalNat Commun
PubMed ID31919418
PubMed Central IDPMC6952380
Grant ListRG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
MR/N003284/1 / MRC_ / Medical Research Council / United Kingdom
14136 / CRUK_ / Cancer Research UK / United Kingdom
G0401527 / MRC_ / Medical Research Council / United Kingdom
MR/K006584/1 / MRC_ / Medical Research Council / United Kingdom
MC_PC_13040 / MRC_ / Medical Research Council / United Kingdom
MR/S003754/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL139731 / HL / NHLBI NIH HHS / United States
RG/18/13/33946 / BHF_ / British Heart Foundation / United Kingdom
PCL/17/07 / CSO_ / Chief Scientist Office / United Kingdom
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
RG/10/12/28456 / BHF_ / British Heart Foundation / United Kingdom
SP/13/6/30554 / BHF_ / British Heart Foundation / United Kingdom