Objective To investigate the causal association between female reproductive behavior and functional gastrointestinal disorders (FGIDs) using Mendelian randomization (MR).

Methods Based on genome-wide association study (GWAS) data, two-sample MR analysis was used to explore the genetic association between female reproductive behavior and FGIDs. Body mass index, major depressive disorder, and educational level were chosen as mediators, and a two-step MR analysis was performed to quantify the proportions of these associations mediated by each factor.

Results Two-sample MR analysis showed that later age at menarche [OR=0.87, 95%CI (0.77, 0.98), P=0.026] and menopausal status [OR=0.41, 95%CI (0.20, 0.85), P=0.016] were nominally associated with a reduced risk of functional constipation (P_FDR > 0.05); earlier age at first live birth [OR=0.51, 95%CI (0.34, 0.77), P=0.001] and earlier age at first sexual intercourse [OR=0.61, 95%CI (0.49, 0.77), P < 0.001] were both significantly associated with an increased risk of irritable bowel syndrome (IBS) (P_FDR < 0.05). Additionally, age at first sexual intercourse also showed nominal associations with functional constipation and functional dyspepsia, and number of live births showed nominal associations with functional constipation and IBS (all P < 0.05, P_FDR > 0.05). The two-step MR analysis further demonstrated that major depressive disorder and educational attainment mediated 35.81% and 21.32% of the association between early age at first live birth and IBS, respectively. In the association between earlier age at first sexual intercourse and IBS risk, they mediated 37.57% and 33.77% of the effect, respectively.

Conclusion These findings suggest a negative causal relationship between age at menarche or menopausal status and functional constipation, between the age at first live birth or age at first sexual intercourse and IBS, between age at first sexual intercourse and functional constipation or functional dyspepsia, and between the number of live births and functional constipation or IBS, with mechanisms involving major depressive disorder and educational attainment potentially underlying this association.

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