Genetic Causal Association Between Vitamin E and Depression: A Two‐Sample Mendelian Randomization Study

BACKGROUND AND PURPOSE: Evidence regarding the association between vitamin E and depression is inconsistent. To address this uncertainty, we employed a two-sample Mendelian randomization (MR) approach to evaluate the potential causal effect of vitamin E on depression risk. METHODS: Genetic associations for vitamin E and depression were obtained from large-scale, publicly available genome-wide association studies (GWAS). We applied five complementary MR methods: inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode, with IVW serving as the primary analysis. To evaluate the robustness of our findings, we performed sensitivity analyses including Cochran's Q test, the MR-Egger intercept test, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), and leave-one-out analyses. RESULTS: In total, nine single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs). Across all MR methods, the odds ratios (ORs) were statistically non-significant (P > 0.05): IVW (OR = 3.67, 95% CI: 0.85-15.85, p = 0.082), MR-Egger (OR = 28.77, 95% CI: 1.05-786.24, p = 0.087), weighted median (OR = 4.44, 95% CI: 0.73-6.97, p = 0.105), simple mode (OR = 1.29, 95% CI: 0.08-21.79, p = 0.866), and weighted mode (OR = 1.29, 95% CI: 0.08-21.84, p = 0.866). The robustness of these null findings was supported by subsequent sensitivity analyses. CONCLUSIONS: The present MR analysis indicated that genetically predicted vitamin E was not causally associated with the risk of depression. However, a non-linear association cannot be excluded and thus merits further investigation.