Micronutrients in psychiatric and neurodevelopmental disorders

Purpose: Micronutrients are essential for brain function, but whether their reported associations with psychiatric and neurodevelopmental disorders are causal remains unclear. We evaluated these associations systematically by integrating evidence from an umbrella review and Mendelian randomization (MR) analyses.Methods: Systematic searches of PubMed and Embase (PROSPERO CRD42023468700) identified 26 eligible meta-analyses of observational studies. MR analyses examined 14 micronutrients and 12 disorders using genome-wide association summary statistics from individuals of European ancestry, with sensitivity analyses including weighted median, MR-Egger, and MR-PRESSO.Results: Among 168 micronutrient–disorder associations, none reached statistical significance in both observational and MR analyses. Several associations showed directionally consistent patterns across independent observational studies or between observational and MR results, but only zinc–autism spectrum disorder (ASD) and vitamin D–major depressive disorder (MDD) were concordant across both evidence streams. Individuals with ASD had lower circulating zinc levels than controls (standardized mean difference, –0.36; 95% confidence interval [CI], –0.67 to –0.05), while genetically predicted higher zinc levels showed a suggestive association with lower ASD risk (odds ratio [OR], 0.91; 95% CI, 0.83 to 1.00; P= 0.055). For vitamin D–MDD, observational evidence indicated lower serum vitamin D levels in MDD (Hedges’ g, –0.35; 95% CI, –0.49 to –0.20), with a concordant but non-significant MR estimate (OR, 0.92; 95% CI, 0.83 to 1.01; P= 0.085).Conclusion: MR provided limited evidence for causality, suggesting that observed micronutrient differences may largely reflect the downstream effects of psychiatric illness. Zinc–ASD and vitamin D–MDD warrant further longitudinal and interventional investigation.