Abstract 17030: Phenome-Wide Mapping of Genetic Effects Distinguishes Etiological Modules Underlying the Phenotypic Spectrum of Heart Failure

Abstract

Introduction: The heart failure (HF) syndrome has been associated with multiple risk factors of which causal effects on conventional HF subtypes remain unclear. Leveraging insights from human genetics, we characterized the associations of genetic loci associated with susceptibility to HF across a wide range of risk factors and diseases to identify causal risk factors and etiological modules underlying HF subtypes. Methods: Through a genome-wide association meta-analysis in 1.9 million individuals, we identified 66 independent genetic susceptibility loci across HF subtypes. We evaluated the pleiotropic effects of these loci across 294 disease phenotypes in 400,000 UK Biobank participants. Using graph modeling, we constructed a pleiotropy network of HF loci and identified distinct etiological clusters based on the network topology. Finally, we performed cross-trait genetic colocalization, genetic correlation, and Mendelian randomization analyses to investigate the causal effects of 24 HF-related phenotypes across HF subtypes. Results: We identified 207 associations between 49 genetic susceptibility loci of HF and 79 disease phenotypes. Network analysis revealed 18 distinct etiological clusters underlying these associations (Figure A), including clusters of interlinked ischemic phenotypes, cardiac arrhythmia / cardiomyopathies, hypertension, and diabetes / obesity. Through colocalization analysis, we found 105 causal genetic variants that are shared between HF and at least one other trait at 42 loci. We observed differential patterns of genetic correlation and causal associations, for instance, type 2 diabetes were genetically correlated to all HF subtypes but not causally associated with any (Figure B). Conclusions: Genetic analysis identifies distinct etiological modules and causal risk factors underlying different forms of HF, providing insights that may inform approaches to treatment and prevention.