Abstract 4373583: Exome Wide Rare Variant Analysis Identifies Novel Genes Associated with Coronary Artery Disease

Background: Cardiovascular disease is a leading cause of morbidity and mortality worldwide, and coronary artery disease is its most common subtype. While common variants have been extensively studied, much of the genetic architecture of coronary artery disease remains unexplained. Rare coding variants offer an opportunity to discover novel disease-associated genes with direct biological relevance. Research question: Can we identify genes carrying rare loss of function variants associated with coronary artery disease, and what are their broader cardiometabolic effects? Methods: We analyzed sequencing data from three large biobanks including UK Biobank with 59,236 cases and 422,329 controls, All of Us with 48,395 cases and 267,650 controls, and Mass General Brigham Biobank with 10,400 cases and 39,888 controls, totaling over 847,000 individuals. We performed gene-based burden testing aggregating rare loss of function variants to identify genes associated with coronary artery disease. Our mixed effects models were adjusted for age, sex, population structure, and relatedness. Genes reaching statistical significance (P<3.20x10 -6 ) were further evaluated using phenome-wide association of 1587 PheCodes and 7 cardiometabolic traits. Results: Six genes were significantly associated with coronary artery disease: LDLR (OR 4.74 P=1.06 ×10 -19 ), TTN (OR 1.49, P=8.59x10 -22 ), PKD1 (OR 1.67, P=1.25×10 -6 ), ADGRL1 (OR 4.2, P=7.24x10 -7 ), RMC1 (OR 2.84, P=1.58×10 -6 ), and RBM12 (OR 3.46, P=2.63×10 -6 ). ADGRL1, RMC1, and RBM12 showed significant associations despite no prior implication in coronary or cardiometabolic traits, in contrast to LDLR , TTN and PKD1 , which have established roles. Phenome wide analysis revealed links between the novel genes and conditions such as hypertension, obesity, diabetes, and arrhythmias. Risk factor analyses showed that ADGRL1 and RMC1 were associated with higher body mass index and triglycerides and lower high density lipoprotein cholesterol. RBM12 was additionally associated with elevated low density lipoprotein cholesterol. Conclusions and Relevance: We identified five novel genes associated with coronary artery disease through exome wide rare variant analysis. Follow up phenome wide and risk factor analyses suggest functional relevance, particularly for ADGRL1 , RMC1 , and RBM12 , offering new biological insights into coronary artery disease.