Abstract
BACKGROUND AND OBJECTIVES: In observational studies, women's fertility and sexual development traits may have implications for DNA methylation patterns, and pregnancy-related risk factors can also affect maternal DNA methylation patterns. The aim of our study is to disentangle any potential causal associations between women's fertility and sexual development traits and epigenetic clocks, as well as to search for probable mediators by using the Mendelian randomization (MR) method. METHODS: Instrumental variables for exposures, mediators, and outcomes were adopted from genome-wide association studies data of European ancestry individuals. The potential causal relationship between women's fertility and sexual development traits and four epigenetic clocks were evaluated by inverse variance weighted method and verified by other two methods. Furthermore, we employed multivariable MR (MVMR) adjusting for hypertension, hyperglycemia, BMI changes, and insomnia. Then, combining the MVMR results and previous research, we performed two-step MR to explore the mediating effects of BMI, AFS, and AFB. Multiple sensitivity analyses were further performed to verify the robustness of our findings. RESULTS: Leveraging two-sample MR analysis, we observed statistically significant associations between earlier age at first birth (AFB) with a higher HannumAge, PhenoAge and GrimAge acceleration(β = - 0.429, 95% CI [- 0.781 to - 0.077], p = 0.017 for HannumAge; β = - 0.571, 95% CI [- 1.006 to - 0.136], p = 0.010 for PhenoAge, and β = - 1.136, 95% CI [- 1.508 to - 0.765], p = 2.03E-09 for GrimAge respectively) and age at first sexual intercourse (AFS) with a higher HannumAge and GrimAge acceleration(β = - 0.175, 95% CI [- 0.336 to - 0.014], p = 0.033 for HannumAge; β = - 0.210, 95% CI [- 0.350 to - 0.070], p = 0.003 for GrimAge, respectively). Further analyses indicated that BMI, AFB and AFS played mediator roles in the path from women's fertility and sexual development traits to epigenetic aging. CONCLUSIONS: Our study suggested that AFS and AFB are associated with epigenetic aging. These findings may prove valuable in informing the development of prevention strategies and interventions targeted towards women's fertility and sexual development experiences and their relationship with epigenetic aging-related diseases.