Causal Relationships Between Epilepsy, Anti-Epileptic Drugs, and Serum Vitamin D and Vitamin D Binding Protein: A Bidirectional and Drug Target Mendelian Randomization Study.

Aims: Previous studies suggest potential associations between epilepsy, anti-epileptic drugs (AEDs), and levels of vitamin D and vitamin D-binding protein (VDBP). This study aims to investigate the causal relationships among these variables using Mendelian Randomization (MR) methods.

Methods: Using summary data from genome-wide association studies on serum 25-hydroxyvitamin D [25(OH)D] levels (N = 417,580), VDBP concentrations (N = 65,589), and various types of epilepsy (Ncases = 27,559), MR analyses were conducted to determine bidirectional causal relationships among these variables. Additionally, eQTL data from eQTLGen (N = 31,684) were employed to model the effects of AEDs and evaluate their causal impact on both biomarkers.

Results: No causal relationships were found between serum 25(OH)D or VDBP levels and epilepsy. Although genetically predicted focal epilepsy risk was potentially associated with increased serum 25(OH)D levels (OR 1.031, 95% CI: 1.006-1.058, p = 0.017), and a higher genetic risk of juvenile myoclonic epilepsy was linked to lower VDBP levels (OR 0.977, 95% CI: 0.961-0.993, p = 0.004), both associations lost significance after multiple correction. Furthermore, significant associations were observed between serum 25(OH)D levels and AED target genes SCN4A, GABBR1, CA13, ALDH5A1, and CA8. No significant associations were found between AED target genes and VDBP levels after correction.

Conclusion: No causal relationships were found between genetically determined serum 25(OH)D levels, VDBP, and epilepsy or its subtypes. Furthermore, the use of AEDs, such as Carbamazepine, Oxcarbazepine, Progabide, and Valproic Acid, reduces serum 25(OH)D levels, while not affect VDBP levels.