Novel Epistatic Interaction Between RBMS3 and CDKN2B-AS1 in Coronary Artery Disease Risk Identified by Machine Learning Tool VariantSpark

Genome-wide association studies (GWAS) of coronary artery disease (CAD), the leading cause of mortality and morbidity globally, have identified approximately 163 risk loci, yet only 40% of CAD genetic heritability can be explained. Non-additive genetic effects, like epistasis, likely contribute to CAD aetiology, but remain elusive due to limited data and insensitive algorithms. Using machine-learning (VariantSpark) followed by exhaustive epistasis search (BitEpi), we discovered an epistatic interaction for CAD between RBMS3 and CDKN2B-AS1 in the UK Biobank. We also observe this interaction in the independent All of Us cohort and provide a binding model using AlphaFold3. VariantSpark provides the needed sensitivity, identifying associated loci (e.g. PMAIP1-MC4R and AAK1) with 72% fewer samples than previous studies, to reduce the search space for systematic epistasis detection. We provide in silico evidence of RBMS3 as a novel CAD risk gene, acting in epistasis with the established CDKN2B-AS1 9p21.3 risk loci.