Modifiable risk factors for epilepsy: A two‐sample Mendelian randomization study

INTRODUCTION: We conducted a two‐sample Mendelian randomization study to determine the associations of modifiable risk factors with epilepsy. METHODS: Fourteen potential risk factors for epilepsy were selected based on a systematic review of risk factors for epilepsy. Single‐nucleotide polymorphisms associated with each exposure at the genome‐wide significance threshold (p < 5×10(–8)) were proposed as instrumental variables from corresponding genome‐wide association studies. Summary‐level data for epilepsy were obtained from the FinnGen consortium (4,588 cases and 144 780 noncases). Potential causal associations (p < .05) were attempted for replication using UK Biobank data (901 cases and 395 209 controls). RESULTS: Among 14 potential risk factors, 4 showed significant associations with epilepsy in FinnGen. All associations were directionally similar in UK Biobank and associated with epilepsy at p ≤ .004 in meta‐analyses of FinnGen and UK Biobank data. The odds ratios of epilepsy were 1.46 (95% CI, 1.18, 1.82) for one unit increase in log odds ratio of having depression, 1.44 (95% CI, 1.13, 1.85) for one standard deviation increase in serum ferritin, 1.12 (95% CI, 1.04, 1.21) for one standard deviation increase in transferrin saturation, and 1.25 (95% CI, 1.09, 1.43) for one standard deviation increase in the prevalence of smoking initiation. There were suggestive associations of serum iron and magnesium with epilepsy. No association was observed for insomnia, blood pressure, alcohol consumption, or serum vitamin B12, 25‐hydroxyvitamin D and calcium levels. CONCLUSION: This MR study identified several modifiable risk factors for adulthood epilepsy. Reducing prevalence of depression and smoking initiation should be considered as primary prevention strategies for epilepsy.