Genetic prediction of age at menarche, age at natural menopause and type 2 diabetes: A Mendelian randomization study.

Background And Aims: The relationship between reproductive factors and type 2 diabetes (T2D) is controversial; therefore, we explored the causal relationship of age at menarche (AAM), age at natural menopause (ANM), with the risk of T2D and glycemic traits using two-sample Mendelian randomization.

Methods And Results: We used publicly available data at the summary level of genome-wide association studies, where AAM (N = 329,345), ANM (N = 69,360), T2D (N = 464,389). The inverse variance weighting (IVW) method was employed as the primary method. To demonstrate the robustness of the results, we also conducted various sensitivity analysis methods including the MR-Egger regression, the weighted median (WM) and the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. After excluding IVs associated with confounders, we found a causal association between later AAM and reduced risk of T2D (OR 0.81 [95% CI 0.75, 0.87]; P = 2.20 × 10), lower levels of FI (β -0.04 [95% CI -0.06, -0.01]; P = 2.19 × 10), FPG (β -0.03 [95% CI -0.05, -0.007]; P = 9.67 × 10) and HOMA-IR (β -0.04 [95% CI -0.06, -0.01]; P = 4,95 × 10). As for ANM, we only found a causal effect with HOMA-IR (β -0.01 [95% CI -0.02, -0.005]; P = 1.77 × 10), but not with T2D.

Conclusions: Our MR study showed a causal relationship between later AAM and lower risk of developing T2D, lower FI, FPG and HOMA-IR levels. This may provide new insights into the prevention of T2D in women.