Multi-omics pleiotropic association analyses reveal functionally relevant genes and druggable pathways for ovarian aging

BACKGROUND: Ovarian aging, marked by the gradual decline in both the number and quality of oocytes, significantly impacts women's reproductive lifespan and overall health. However, the biological mechanisms driving ovarian aging remain poorly understood and current treatment strategies are limited. RESULTS: We perform an integrative analysis using multi-omics summary data and genome-wide association studies for ovarian aging to identify molecular traits linked to ovarian aging. By applying Mendelian randomization and cross-omics association approaches, we prioritize key proteins, gene expressions, splicing events, and metabolites. Our analysis identifies conservation of key genes across species and cell types, with the mismatch repair gene MSH6 (MutS Homolog 6) emerging as a consistently prioritized candidate. Experimental validation shows that targeting DNA repair through PD-L1 (Programmed Death-Ligand 1) blockade may offer a potential therapeutic strategy to delay ovarian aging. CONCLUSIONS: This study uncovers the multi-layered genetic and molecular architecture underlying ovarian aging. The identified molecular traits provide promising candidates for functional studies and suggest new avenues for developing therapies aimed at preserving ovarian function and preventing age-related decline.