Causal Influences of Micronutrients on Anxiety: Insights From an Observational and Mendelian Randomization Analysis

An increasing number of studies have begun to focus on the role of micronutrients (vitamins and minerals) in mental disorders, including anxiety. Previous observational and clinical studies have suggested a relationship between micronutrients and anxiety, yet the causal link between them remains unclear. We aimed to detect the potential causal relationships between genetically predicted supplementation with vitamins (including vitamins A, B, B6, B12, C, D, E, folate, and multivitamins), minerals (including calcium, iron, magnesium, selenium, and zinc), and anxiety through Mendelian randomization (MR) analysis, the Bayesian colocalization analysis, and real-world observational data. Summary genome-wide association study datasets covering various supplements from the UK Biobank (N = 64,979 ~ 462,933) and anxiety (N = 346,542) from the FinnGen project R10 were utilized in our MR analyses. Then, the Bayesian colocalization analysis was used to validate the MR findings. Finally, we analyzed the association between micronutrients and anxiety by mining the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database (2004Q1 ~ 2024Q2). IVW-based MR study revealed the significant protective effects of vitamin C (OR: 0.38, p = 0.032), magnesium (OR: 0.15, p = 0.035), and selenium (OR: 0.03, p = 0.020) against anxiety disorders. However, the colocalization analysis did not provide any evidence of shared causal variants between supplementation with vitamin C, magnesium, selenium, and anxiety disorders. Analysis of the FAERS database showed that vitamin C (ROR: 0.30, 95% CI: 0.16-0.59, p = 0.0002) and magnesium use (ROR: 0.32, 95% CI: 0.18-0.57, p < 0.0001) were associated with decreased risks of anxiety; while no cases of anxiety were reported for selenium use. Our study provides suggestive genetic evidence of the causal protective role of vitamin C, magnesium, and selenium on the risk of anxiety and supports targeting anxiety phenotypes with nutritional interventions.