Causal effects of reproductive traits on cognitive function: A two‐sample and multivariable mendelian randomization study

OBJECTIVE: Potential associations between reproductive traits and cognitive function have been discovered; however, the results are inconsistent, and the causalities are unclear. This study utilized Mendelian randomization (MR) analysis to assess the causal impact of reproductive traits on cognitive function. METHODS: We performed two-sample univariable MR (UVMR) and multivariable MR (MVMR) approach to assess genetic causal associations among reproductive traits and cognitive function. We used the inverse variance weighted (IVW) method to explore the role of reproductive traits on cognitive function in the primary analyses, followed by several sensitivity analyses for robustness of our findings. In addition, we conducted MVMR analyses to assess whether the direct causal effects were independent of two modifiable risk factors: body mass index (BMI) and educational attainment (EA). RESULTS: UVMR analysis showed a younger age at first sexual intercourse (AFS) was significantly associated with poorer cognitive function across multiple domains. A earlier age at first birth (AFB) was significantly associated with poorer cognitive outcomes, including lower cognitive performance (β = 0.116, 95% confidence interval [CI]: 0.087 to 0.146, P < 0.001, IVW), reduced fluid intelligence score (β = 0.248, 95% CI: 0.186 to 0.309, P < 0.001, IVW), and diminished memory performance (β = 0.042, 95% CI: 0.012 to 0.071, P = 0.006, IVW). After further adjustment for BMI or EA, the associations remained significant. Genetically predicted hormone replacement therapy (HRT) use was associated with cognitive decline, including longer completion time in the Pairs Matching (PM) test and fewer correct and attempted matches in the Symbol Digit Substitution (SDS) test; however, after further adjustment for premature menopause, premature ovarian insufficiency, age at HRT initiation, and duration of use, there was insufficient evidence to support a causal association between HRT use and cognitive decline. CONCLUSION: Our UVMR and MVMR analyses provide evidence that earlier AFS and earlier AFB are risk factors for cognitive decline. The protective effect of oral contraceptive pills and fewer number of live births on cognitive function is partly influenced by EA. These findings emphasize the important role of reproductive traits in influencing cognitive function.