Objectives:Several studies have indicated a potential association between early life course-related traits and neurological and psychiatric disorders in adulthood, but the causal link remains unclear.Methods:Instrumental variables (IVs) that have been shown to be strongly associated with exposure were obtained from summary data of genome-wide association studies (GWASs). Four early life course-related traits [i.e., birthweight (BW), childhood body mass index (BMI), early body size, and age at first birth (AFB)] were used as exposure IVs to estimate their causal associations with three neurological and psychiatric diseases [i.e., Alzheimer’s disease (AD), major depressive disorder (MDD), and attention-deficit hyperactivity disorder (ADHD)]. Four different statistical methods, i.e., inverse-variance weighting (IVW), MR–Egger (MRE), weighted median (WM), and weighted mode (Wm), were performed in our MR analysis. Sensitivity analysis was performed by using the leave-one-out method, and horizontal pleiotropy was assessed using the MR-PRESSO package.Results:There was evidence suggesting that BW has a causal effect on AD (ORMR-PRESSO = 1.05, p = 1.14E-03), but this association was not confirmed via multivariable Mendelian randomization (MVMR) (ORMVMR = 0.97, 95% CI 0.92–1.02, p = 3.00E-01). A strong relationship was observed between childhood BMI and ADHD among both sexes; a 1-SD increase in BMI significantly predicted a 1.46-fold increase in the OR for ADHD (p = 9.13E-06). In addition, a similar relationship was found between early life body size and ADHD (ORMR-PRESSO = 1.47, p = 9.62E-05), and this effect was mainly driven by male participants (ORMR-PRESSO = 1.50, p = 1.28E-3). Earlier AFB could significantly predict a higher risk of MDD (ORMR-PRESSO = 1.19, p = 1.96E-10) and ADHD (ORMR-PRESSO = 1.45, p = 1.47E-15). No significant causal associations were observed between the remaining exposures and outcomes.Conclusion:Our results reveal the adverse effects of childhood obesity and preterm birth on the risk of ADHD later in life. The results of MVMR also show that lower BW may have no direct relationship with AD after adjusting for BMI. Furthermore, AFB may predict a higher risk of MDD.

Objective: A number of epidemiological studies have demonstrated that smoking initiation and alcohol and coffee consumption were closely related to women’s reproductive health. However, there was still insufficient evidence supporting their direct causality effect.Methods: We utilized two-sample Mendelian randomization (TSMR) analysis with summary datasets from genome-wide association study (GWAS) to investigate the causal relationship between smoking initiation, alcohol and coffee consumption, and women’s reproductive health-related traits. Exposure genetic instruments were used as variants significantly related to traits. The inverse-variance weighted (IVW) method was used as the main analysis approach, and we also performed MR-PRESSO, MR-Egger, weighted median, and weighted mode to supplement the sensitivity test. Then, the horizontal pleiotropy was detected by using MRE intercept and MR-PRESSO methods, and the heterogeneity was assessed using Cochran’s Q statistics.Results: We found evidence that smoking women showed a significant inverse causal association with the sex hormone-binding globulin (SHBG) levels (corrected β = −0.033, p = 9.05E-06) and age at menopause (corrected β = −0.477, p = 6.60E-09) and a potential positive correlation with the total testosterone (TT) levels (corrected β = 0.033, p = 1.01E-02). In addition, there was suggestive evidence for the alcohol drinking effect on the elevated TT levels (corrected β = 0.117, p = 5.93E-03) and earlier age at menopause (corrected β = −0.502, p = 4.14E-02) among women, while coffee consumption might decrease the female SHBG levels (corrected β = −0.034, p = 1.33E-03).Conclusion: Our findings suggested that smoking in women significantly decreased their SHBG concentration, promoted earlier menopause, and possibly reduced the TT levels. Alcohol drinking had a potential effect on female higher TT levels and earlier menopause, while coffee consumption might lead to lower female SHBG levels.