Causal link between oxidative stress and epilepsy: A two‐sample Mendelian randomization study

Abstract

BackgroundAlthough a growing body of research has indicated a strong link between oxidative stress and epilepsy, the exact nature of their interaction remains elusive. To elucidate this intricate relationship, we conducted a bidirectional Mendelian randomization (MR) analysis employing two independent datasets.MethodsA two‐sample MR analysis was performed using instrumental variables derived from genome‐wide association study summary statistics of oxidative stress injury biomarkers (OSIB) and epilepsy. The OSIBs were selected from eight primary metabolic pathways associated with oxidative stress. Additionally, seven distinct epilepsy phenotypes were considered, which encompassed all epilepsy, generalized epilepsy, generalized tonic‐clonic seizures, focal epilepsy, focal epilepsy with hippocampal sclerosis (focal HS), focal epilepsy with lesions other than HS (focal NHS), and lesion‐negative focal epilepsy. Causal estimates were computed using the inverse‐variance weighted method or the Wald ratio method, and the robustness of causality was assessed through sensitivity analyses.ResultsFor OSIB and epilepsy, 520 and 23 genetic variants, respectively, were selectively extracted as instrumental variants. Genetically predicted higher kynurenine level was associated with a decreased risk of focal epilepsy (odds ratio [OR] 1.950, 95% CI 1.373–2.528, p = .023) and focal NHS (OR 1.276, 95% CI 1.100–1.453, p = .006). For reverse analysis, there was a suggestive effect of focal NHS on urate (OR 1.19 × 1015, 95% CI 11.19 × 1015 to 1.19 × 1015, p = .0000746) and total bilirubin (Tb) (OR 4.98, 95% CI 3.423–6.543, p = .044). In addition, genetic predisposition to focal HS was associated with higher Tb levels (OR 9.83, 95% CI 7.77–11.888, p = .034).ConclusionThis MR study provides compelling evidence of a robust association between oxidative stress and epilepsy, with a notable emphasis on a causal relationship between oxidative stress and focal epilepsy. Additional research is warranted to confirm the connection between oxidative stress and the risk of epilepsy and to unravel the underlying mechanisms.