Investigating Causal Associations of Diet-Derived Circulating Antioxidants with Risk of Six Major Mental Disorders: A Mendelian Randomization Study

Abstract Background Observational studies have suggested associations between circulating antioxidant levels and many mental disorders, but evidence from randomized controlled trials (RCTs) is lacking and causal inferences have not been confirmed. The aim of this study was to explore whether genetically predicted diet-derived circulating antioxidants were causally associated with the risk of major mental disorders using Mendelian randomization (MR). Methods and findings We performed 2-sample MR analyses of summary-level genetic data to explore whether diet-derived circulating antioxidants [e.g., vitamins E (α- and γ-tocopherol), ascorbate, retinol, β-carotene, and lycopene], assessed by absolute circulating antioxidants and relative circulating antioxidant metabolites, were causally associated with the risk of six major mental disorders, including major depressive disorder (MDD), schizophrenia (SCZ), bipolar disorder (BIP), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and post-traumatic stress disorder (PTSD). The inverse-variance weighted method was adopted as primary MR analyses and five additional MR methods (likelihood-based MR, MR-Egger, weighted median, penalized weighted median, and MR-PRESSO) and different outcome databases were used for sensitivity analyses. We found suggestive evidence that genetically predicted higher absolute circulating α-tocopherol levels marginally reduced the risk of SCZ, with the odds ratio (OR) per unit increase in log-transformed α-tocopherol values was 0.71 [95% confidence interval (CI) 0.54 to 0.94; P = 0.016]. However, after adjusting for multiple testing (threshold of P < 0.008), we found no significant evidence that genetically predicted higher diet-derived absolute circulating antioxidant levels and antioxidant metabolites concentrations were significantly causally associated with the six-foregoing major mental disorders. Conclusions Overall, our study does not support significant causal associations of genetically predicted diet-derived circulating antioxidants with the risk of major mental disorders. Therefore, simply taking antioxidants to increase blood antioxidants levels is unlikely to have a significant protective effect on the prevention of most mental disorders. Author summary Why was this study done? Some observational studies have reported that diet-derived circulating antioxidants are associated with a reduced risk of major mental disorders; however, these studies are susceptible to uncertain temporal relationships, insufficient sample sizes, or potential confounding factors, and thus it remains unclear whether these associations are accurate. To our knowledge, there are no randomized clinical trials published to date on this topic. Since oxidative stress is closely related to the occurrence of mental diseases, if diet-derived circulating antioxidants can reduce the risk of major mental disorders, it will be an interesting target as primary prevention of mental disorders. What did the researchers do and find? We performed a Mendelian randomization study design to explore whether genetically predicted diet-derived circulating antioxidants [e.g., vitamins E (α- and γ-tocopherol), ascorbate, retinol, β-carotene, and lycopene], assessed by absolute circulating antioxidants and relative circulating antioxidant metabolites, were causally associated with the risk of six major mental disorders, including major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder, attention- deficit/hyperactivity disorder, and post-traumatic stress disorder. Overall, our study provides suggestive evidence that genetically predicted higher absolute α-tocopherol levels may be causally associated with a reduced risk of schizophrenia. However, our study did not find genetically predicted significant causal associations of dietary antioxidants with major mental disorders after correction for multiple testing. What do these findings mean? Our findings suggest for healthy adults without nutritional deficiency, simply taking antioxidants to increase blood antioxidants levels is unlikely to have a significant protective effect on the prevention of most mental disorders. In the future, large-scale GWASs are needed to further validate our current findings, especially the suggestive protective effect of higher α-tocopherol levels on schizophrenia, by utilizing additional genetic variants and more samples.

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