Exploring the causal relationship between female reproductive traits and asthma: A bidirectional two-sample Mendelian randomization study in a European population

Epidemiological studies have reported gender disparities in asthma, suggesting female reproductive traits may play a role, though causality remains unclear. We used summary data from genome-wide association studies on 12 female reproductive traits and asthma (408,422 European individuals). Univariate (UVMR) and multivariate Mendelian randomization (MVMR) analyses were performed using inverse-variance weighted (IVW) as the primary method. Supplementary methods included MR-Egger, weighted median, and robust adjusted profile score for UVMR, and MVMR-Lasso and MVMR-median for MVMR. Sensitivity analyses were conducted to validate findings. We acknowledge that MR estimates rely on key assumptions (relevance, independence, exclusion restriction), and violations may bias causal inference. After Bonferroni correction, UVMR-IVW showed that later age at first sexual intercourse (AFS) significantly reduced asthma risk (OR = 0.663, 95% CI = 0.603-0.729, P < .001). Later age at first birth (AFB) (OR = 0.893, 95% CI = 0.862-0.926, P < .001) and last birth (ALB) (OR = 0.845, 95% CI = 0.755-0.946, P < .001) were also protective. Age at menarche (AAM) showed a nominally significant inverse association (OR = 0.968, 95% CI = 0.94-0.998, P = .034), while hormone replacement therapy (HRT) use increased asthma risk (OR = 1.435, 95% CI = 1.05-1.962, P = .024). No causal links were found for age at natural menopause, live births, stillbirths, miscarriages, hysterectomy, oophorectomy, or oral contraceptive use. In MVMR analyses adjusted for body mass index (BMI), educational attainment, smoking, and Townsend deprivation index, the protective effects of AFS (OR = 0.678, 95% CI = 0.552-0.833, P < .001) and AFB (OR = 0.933, 95% CI = 0.874-0.995, P = .033) persisted. Mediation analysis indicated BMI partially mediated the AFS and AFB-asthma associations. This MR study provides evidence consistent with a causal effect of earlier AFS and AFB on increased asthma risk, partially mediated by BMI. These findings underscore the potential importance of reproductive and metabolic health in asthma prevention strategies.