ObjectiveThe observational studies indicate an association between obesity and epilepsy, but it is unclear whether such an association responds to causality. The objective of this study was to determine the causal relationship between obesity and fat distribution and epilepsy subtypes based on waist circumference, hip circumference (HP), waist-hip ratio (WHR), and body mass index (BMI).MethodsA two-sample Mendelian randomization study was conducted separately for the four indicators of obesity and epilepsy and its seven subtypes, with reverse Mendelian randomization and multivariate Mendelian randomization for significant outcomes.ResultsA two-sample Mendelian randomized analysis informed us that waist circumference was a risk factor for juvenile myoclonic epilepsy (beta = 0.0299, P = 4.60 × 10−3). The increase in hip circumference increased the risk of juvenile myoclonic epilepsy and epilepsy, with effect values of 0.0283 (P = 2.01 × 10−3) and 0.0928 (P = 1.40 × 10−2), respectively. Furthermore, children with a higher BMI exhibit a higher risk of epilepsy (beta = 0.0148 P = 1.05 × 10−3). The reverse Mendelian randomization study revealed that childhood absence epilepsy increased its BMI (beta = 0.8980, P = 7.52 × 10−7), and juvenile myoclonic epilepsy increased its waist circumference (beta = 0.7322, P = 3.26 × 10−2). Multivariate Mendelian randomization revealed that an increase in hip circumference and waist-hip ratio increased the risk of juvenile myoclonic epilepsy, with an effect value of 0.1051 (P = 9.75 × 10−4) and 0.1430 (P = 3.99 × 10−3), respectively, while an increase in BMI and waist circumference instead decreased their risk, with effect values of −0.0951 (P = 3.14 × 10−2) and−0.0541 (P = 1.71 × 10−2). In contrast, multivariate Mendelian randomization for childhood absence epilepsy and epilepsy did not identify any independent risk factors.SignificanceOur findings provide novel evidence in favor of obesity as a risk factor for epilepsy and waist circumference as a risk factor for juvenile myoclonic epilepsy. Increased hip circumference confers an elevated risk of juvenile myoclonic epilepsy and epilepsy (all documented cases), and a high BMI increases the risk of childhood absence epilepsy. With this, new insights are provided into the energy metabolism of epilepsy, which supports further nutritional interventions and the search for new therapeutic targets.

Diabetes has been linked to an increased risk of epilepsy in observational studies. The antiglycemic drugs have been shown in animal studies to improve seizures. However, whether the associations between antiglycemic drugs and epilepsy in human is not known. In this study, we conducted a Mendelian randomization investigation to assess the potential causal role of antiglycemic drug targets in epilepsy.We used the International League Against Epilepsy Data as the discovery set and FinnGen Data as the replication set .Three antidiabetic drug target genes, including ETFDH, CYP21A2, and CYP2D6 were discovered to be involved in epilepsy. ETFDH predicted as a target gene in the discovery set (IVW, OR = 1.018, 95% CI, 1.004–1.033, p = 0.009), replication set (IVW, OR = 1.074, 95% CI, 1.034–1.114, p = 0.00016) and CYP21A2 gene in the discovery set (IVW, OR = 1.029, 95% CI, 1.005– 1.053, p = 0.016) and replication set (IVW, OR = 1.057, 95% CI, 1.001–1.116, p = 0.045) showed a causal association with an increased risk of epilepsy. In contrast, the CYP2D6 gene was found to be a protective factor for epilepsy in both the discovery set (IVW, OR = 0.0984, 95% CI, 0.969–0.998, p = 0.025) and the replication set (IVW, OR = 0.977, 95% CI, 0.955–1.000, p = 0.046). By searching the pharmacological effects of anti-glucose drug target gene related drugs and binding drugs in DrguBank, Metformin was found to be ETFDH gene inhibitor, showing a potential therapeutic effect on epilepsy.