Assessing the causal association between age at menarche and genetic susceptibility to future gastroesophageal reflux disease risks

Objective: Evidence indicates that menarche onset is associated with various health outcomes. Gastroesophageal reflux disease (GERD) is a prevalent condition, which may be influenced by the age at menarche (AAM). The study aims to investigate the potential causal relationship between the AAM and GERD. Methods: We conducted a two-sample Mendelian randomization (MR) analysis utilizing single nucleotide polymorphisms (SNPs) derived from genome-wide association studies summary statistics for AAM and GERD as instrumental variables. Various MR methods were applied to estimate causal effects, supplemented by sensitivity analyses to assess the robustness of our findings. Results: Overall, 69 SNPs associated with the AAM were used after rigorous selection to ensure absence of linkage disequilibrium or association with confounding factors. The inverse variance-weighted (IVW) method indicated a significant inverse association between genetically predicted AAM and GERD (odds ratio, 0.89; 95 % confidence interval, 0.85–0.94). These findings were consistent across weighted median and weighted mode analyses. The MR-Egger regression analysis suggested no significant directional pleiotropy. Heterogeneity was detected among instrumental variables; however, the leave-one-out sensitivity analysis confirmed the association stability. Conclusion: We provided robust evidence supporting an inverse causal relationship between the AAM and GERD risk.