A multi-trait genome-wide association study of coronary artery disease and subclinical atherosclerosis traits.

Measures of subclinical atherosclerosis, such as coronary artery calcification (CAC) and carotid intima-media thickness (CIMT), reflect the underlying pathophysiology of coronary artery disease (CAD) and are genetically correlated with CAD and related risk factors. Leveraging summary statistics from genome-wide association studies of CAD, CIMT, CAC, type 2 diabetes, low-density lipoprotein cholesterol, and systolic blood pressure, we performed 15 separate multi-trait GWAS to identify shared susceptibility loci and elucidate the pleiotropic architecture underlying atherosclerosis. We identified 442 shared risk loci across all analyses that met an experiment-wide Bonferroni threshold of 3.3 × 10-9, uncovering 195 novel atherosclerosis loci. Multi-trait colocalization confirmed a shared causal signal in 25 shared novel loci for atherosclerosis. Trait-eQTL colocalization identified evidence of a shared causal signal in arterial, subcutaneous adipose, and cardiac tissues, implicating genes such as PRRX2, BNC2, CLIC4, SCAI, and PPP6C, and pathways related to vascular remodeling, inflammation, and metabolic regulation.