Genome-wide analysis of cardiac ventricular phenotypes reveals novel loci and therapeutic targets for heart failure

Abstract

Left and right ventricular imaging measures are essential for heart failure diagnosis and prognostication, yet their genetic architecture remains underexplored. We conduct genome-wide association analyses of twenty left and right cardiovascular magnetic resonance phenotypes in 56,509 UK Biobank participants, including conventional measurements (e.g., volumes/ejection fraction) and novel parameters (left ventricular global function index and myocardial contraction fraction). We identify 200 loci associated with at least one phenotype (P < 5×10-8); 58 being novel. A polygenic risk score for left ventricular global function index negative associates with heart failure in phenome-wide scan. Rare variant analysis reveals enrichment of deleterious variants across 13 genes (P < 2.5×10-6). Colocalisation with heart failure implicates 23 shared loci and bioinformatic analysis prioritises genes including HSPB7, CAMK2D, ALDH2, ENG, and YWHAE. Druggability analysis highlights PDE3A, informing divergent effects of non-selective PDE3 inhibition. In this work, we expand our knowledge of cardiac ventricular genetics, suggesting potential heart failure therapeutic targets.