Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

ABSTRACT Rapid progress of the discovery of genetic loci associated with common, complex diseases has outpaced the elucidation of mechanisms pertinent to disease pathogenesis. To address relevant barriers for coronary artery disease (CAD), we combined genetic discovery analyses with downstream characterization of likely causal variants, genes, and biological pathways. Specifically, we conducted a genome-wide association study (GWAS) comprising 181,522 cases of CAD among 1,165,690 participants. We detected 241 associations, including 54 associations and 30 loci not previously linked to CAD. Next, we prioritized likely causal variants using functionally-informed fine-mapping, yielding 42 associations with fewer than five variants in the 95% credible set. Combining eight complementary predictors, we prioritized 185 candidate causal genes, including 94 genes supported by three or more predictors. Similarity-based clustering underscored a role for early developmental processes, cell cycle signaling, and vascular proliferation in the pathogenesis of CAD. Our analysis identifies and systematically characterizes risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.