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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.
Highlights
Heart failure (HF) is a leading cause of morbidity and mortality worldwide
We identified 12 independent genetic variants, at 11 loci associated with HF at genome-wide significance (P < 5 × 10−8), including 10 loci not previously reported for HF (Fig. 2, Table 1)
We identify 12 independent variant associations for HF risk at 11 genomic loci by leveraging genome-wide data on 47,309 cases and 930,014 controls, including 10 loci not previously associated with HF
Summary
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. 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. We hypothesised that a GWAS of HF with greater power would provide an opportunity for: (i) discovery of genetic variants modifying disease susceptibility in a range of comorbid contexts, both through subtype-specific and shared pathophysiological mechanisms, such as fluid congestion; and (ii) provide insights into aetiology by estimating the unconfounded causal contribution of observationally associated risk factors by Mendelian randomisation (MR) analysis[12]. Our study identifies additional HF risk variants, prioritises putative effector genes and provides a genetic appraisal of the putative causal role of observationally associated risk factors, contributing to our understanding of the pathophysiological basis of HF
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