Multivariate Genomic Analysis Reveals Shared Genetic Architecture and Potential Therapeutic Targets for Atherosclerotic Cardiovascular Disease

Background Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of mortality worldwide and comprises multiple clinical phenotypes, but their shared genetic architecture remains incompletely defined. Methods We integrated genome‐wide association study summary statistics for coronary artery disease, peripheral artery disease, large‐artery atherosclerotic stroke, and carotid plaque using genomic structural equation modeling to derive a multivariable ASCVD common factor. We applied fine‐mapping, multi‐marker analysis of genomic annotation, transcriptome‐wide association studies, Mendelian randomization, colocalization, mediation analysis, and virtual screening. Results We identified 289 linkage disequilibrium–independent lead single‐nucleotide polymorphisms mapping to 177 genomic risk loci; 13 lacked corresponding genome‐wide significant signals in the input genome‐wide association studies. Eleven had prior genome‐wide association study catalog association records, whereas no relevant records were identified for the loci represented by rs2294777 near SASH1 and rs4843053 near AKAP13 . Fine‐mapping prioritized 26 putative causal variants. Integrated functional summary‐based imputation, multi‐tissue transcriptome‐wide association study, and multi‐marker analysis of genomic annotation analyses implicated 123 genes. Enrichment analyses highlighted endothelial cells and H3K27ac‐marked regulatory regions. Lipidomic analyses linked higher triacylglycerols and sterol esters to increased multivariable ASCVD common factor risk. Protein Mendelian randomization analyses in deCODE and Fenland prioritized aldehyde dehydrogenase 2 (ALDH2), phosphodiesterase 5A (PDE5A), HtrAserinepeptidase 1 (HTRA1), and transcription elongation factor A2 (TCEA2) as candidate targets. Colocalization supported a shared causal variant between TCEA2 and multivariable ASCVD common factor. Mediation analyses suggested partial mediation by diastolic blood pressure for ALDH2, PDE5A, and TCEA2 and by triglycerides for TCEA2. Virtual screening identified candidate compounds with favorable predicted binding to PDE5A and ALDH2. Conclusions Integrating multivariate genome‐wide association study with multi‐omics and causal inference analyses identified shared genetic signals associated with ASCVD susceptibility and prioritized candidate protein targets, informing future functional studies and target validation.