Causal association between serum 25-hydroxyvitamin D levels and epilepsy: A two-sample bidirectional mendelian randomization study

Objective

The study aimed to investigate the causal relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and epilepsy using Mendelian randomization (MR), thereby addressing confounding and reverse causality issues in observational studies.

Methods

We employed a two-sample bidirectional MR design utilizing summary-level data from the IEU OpenGWAS project. Serum 25(OH)D levels were analyzed using the publicly available dataset ebi-a-GCST90000618, which included 496,946 European samples and 68,960,93 SNPs. Data on epilepsy were obtained from ebi-a-GCST90018840, comprising 458,310 samples, including 4,382 epilepsy patients and 453,928 controls. To identify instrumental variables (IVs), we applied a significance threshold of P < 5e-8 for serum 25(OH)D levels as the exposure and P < 5e-6 for epilepsy as the exposure. IVs were required to demonstrate an r² < 0.001 linkage disequilibrium and an F-statistic greater than 10. The MR analysis utilized five methods: inverse variance weighted (IVW), weighted median, MR-Egger, weighted mode, and simple mode, assessing causal relationships between serum 25(OH)D levels and epilepsy. Robustness checks included heterogeneity tests, leave-one-out sensitivity analyses, and assessments for horizontal pleiotropy.

Results

Both directions of the MR analysis revealed no genetic correlation between serum 25(OH)D levels and epilepsy.

Conclusion

Our findings, supported by robust IV screening and consistent results across multiple MR methods, indicate a lack of causal relationship between serum 25(OH)D levels and epilepsy. These results suggest that while vitamin D plays a role in the nervous system, its relationship to epilepsy may not be direct, thus highlighting the need for further investigation in future studies.