Shared genetic architecture underlying cataract and cardiovascular disease: insights from multi-omics analyses

Abstract Cataract and cardiovascular disease (CVD) are prevalent age-related disorders with overlapping risk factors. While epidemiological associations are established, the shared genetic mechanisms underlying their comorbidity remain largely unexplored. We performed a comprehensive genome-wide investigation integrating large-scale GWAS summary statistics for age-related cataract and four major CVDs (coronary artery disease, atrial fibrillation, heart failure, and myocardial infarction). Using multi-omics approaches including PLACO, MAGMA, SMR, and colocalization, we identified pleiotropic loci, credible genes, and evaluated their functional relevance. Pathway and gene-set enrichment analyses were conducted to elucidate the underlying biological mechanisms. Significant genetic correlations were found for cataract with AF, CAD, and HF (LDSC and HDL, Bonferroni-corrected P < 0.0125); MI showed method-dependent significance (LDSC P = 0.021, HDL P = 1.71 × 10 −4 ). PLACO identified 924 shared SNPs mapped to 79 loci, of which 12 showed robust colocalization (PP.H4 > 0.8). MAGMA gene-set enrichment revealed pathways related to lipid metabolism, oxidative stress, and vascular development. Gene-based analysis further stratified these into 50 credible genes supported by colocalization or SMR, including TOMM40, APOE, and ATPAF2. Functional enrichment showed these genes were enriched in LXR-mediated cholesterol metabolism, linking systemic and ocular pathophysiology. Our integrative multi-omics analysis reveals substantial genetic overlap between cataract and CVD, identifies pleiotropic genes, and uncovers shared molecular pathways. These findings provide candidate mechanistic hypotheses for the comorbidity of ocular and cardiovascular diseases and highlight candidate genes and pathways that warrant future functional validation.