Identification of potential therapeutic targeting in ovarian aging from genetic screening with clinical validation

PURPOSE: To screen drug targets of ovarian aging from a genetic perspective. METHODS: Systematic analyses were conducted with cis-expression quantitative trait loci data of druggable genes extracted as instrument variables. Summary statistics were from large genome-wide association studies for age at menopause. The following colocalization analysis was utilized to examine whether identified genes and ovarian aging shared causal variants. Furthermore, clinical validation was conducted by comparing expression of identified genes in granulosa cells from women with normal or diminished ovarian reserve (DOR) who went through in vitro fertilization (IVF) and by evaluating correlation of targeted gene expression with ovarian function and IVF outcomes. Moreover, single-nuclear RNA (snRNA) seq and drug database were analyzed to find target cells within the ovary and potential drugs targeting identified genes. RESULTS: Systematic analyses identified five therapeutic targets of ovarian aging, including four protective factors (BRCA1, KLHL18, PNP, SRPK1) and one risk factor (PDIA3). The change in expression level of four protective factors has been verified in clinical validation. Particularly, both BRCA1 and SRPK1 have been downregulated among advanced-aged women with DOR and were positively correlated with anti-Müllerian hormone and antral follicle count. Specific target cells and potential small molecule targeted drugs of these genes were identified through snRNA analysis and searching in the drug database. CONCLUSIONS: By systematic genetic analyses combined with clinical validation, we identified five potential druggable genes for ovarian aging, providing theoretical basis and promising direction of therapeutic genetic targets for ovarian aging in the future.