Causal Relationship Between Vitamin D and Anxiety and Depression: A Bidirectional Mendelian Randomization Study

Abstract

Objective: This study aimed to investigate the causal relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and the risk of depression and anxiety, using Mendelian Randomization (MR) analysis from a genetic variation perspective.

Methods: Genome-wide association study (GWAS) summary statisticsfor 25(OH)D levels, depression and anxiety were retrieved from the IEU Open GWAS Project, specifically from datasets “ebi-a-GCST90000617”, “ebia-GCST90013878”, and “ukb-a-82”. A two-sample MR analysis was conducted with 25(OH)D levels as the exposure and depression and anxiety as outcome variables. Cochran’s Q test was used to assess heterogeneity among the instrumental variables, and horizontal pleiotropy was tested using the MR-Egger intercept method. Sensitivity analyses were conducted via the leave-one-out approach.

Results: The MR analysis, utilizing 32 single nucleotide polymorphisms (SNPs) as instrumental variables, revealed a significant causal association between 25(OH)D levels and depression, with all MR methods (excluding Simple Mode) yielding p-values < 0.05. The odds ratios (ORs) and 95% confidence intervals (CIs) for the significant methods were: OR = 0.82 [95% CI: 0.68–0.98], OR = 0.85 [95% CI: 0.77–0.95], OR = 0.80 [95% CI: 0.68–0.93] and OR = 0.90 [95% CI: 0.82–0.98]. However, no significant causal relationship wasfound between 25(OH)D levels and anxiety. In the reverse direction, genetically predicted depression showed a potential causal association with lower 25(OH)D levels (inverse variance weighting (IVW) OR = 0.98, 95% CI: 0.96–1.00, p = 0.02), while no such association was observed for anxiety.

Conclusions: This study suggests that higher serum 25(OH)D levels may be associated with a lower risk of depression, highlighting the potential of serum 25(OH)D as an early biomarker for depression prevention and clinical management. However, no causal association was found between 25(OH)D levels and anxiety, warranting further investigation. This study provides a potential vitamin Drelated intervention direction for the prevention and clinical management of depression.