Functionality-Informed Fine-Mapping Dissects Common Variant Contributions to Coronary Artery Disease and Identifies Causal Variants and Pathways

Genomics offer a powerful approach to identify causal mechanisms underlying coronary artery disease (CAD) risk, with implications for pathogenesis, personalized prevention strategies, and therapeutic target discovery. Functionality-informed genome-wide fine mapping was performed using the Bayesian framework SBayesRC to estimate genetic contributions of 6.9 million common variants, based on GWAS summary statistics from over one million individuals of European ancestry. Causal candidate genes were prioritized in a 5kB flanking window within high-confidence local credible sets (LCSs). Their downstream biological influence was analyzed using protein-protein interaction networks and pathway enrichment analyses across three complimentary dimensions: molecular, cellular, and disease level. Genetic modeling captured the highly polygenic architecture of CAD, estimating on average 34,000 variants to contribute to CAD risk, explaining 3.8% of total phenotypic variance. 36 high-confidence variants (PIP > 0.9) collectively explained 13.6% of genetic variance, while most variants demonstrated small individual effects but with substantial collective contributions. 17,150 variants were prioritized within 581 high-confidence LCSs, of which 195 were annotated to genes and 170 were implicated in downstream pathway analyses. The three most influential variants were mapped to PHACTR1, APOE, and LPL, explaining 2.49%, 1.59%, and 1.46% of genetic variance respectively. Pathway analyses revealed that genetic risk in CAD is driven by dysregulation of three interlinked biological processes: 1) lipoprotein function and cholesterol metabolism, 2) vascular homeostasis, and 3) cellular stress responses and inflammation. These findings advance the causal understanding of CAD pathogenesis, supporting the transition from association-based to functionality-informed genomic approaches in cardiovascular genetics.