A causal association between gout and uric acid levels and the risk of epilepsy and its subtypes: a two-sample Mendelian randomization study

BACKGROUND: While observational studies have explored the association between gout, uric acid (UA) levels, and the risk of epilepsy, their findings remain inconsistent. OBJECTIVES: To clarify the potential causal relationship, we performed a Mendelian randomization (MR) analysis. MATERIAL AND METHODS: We conducted a bidirectional MR analysis using genome-wide association study (GWAS) summary data. Epilepsy data were sourced from the International League Against Epilepsy (ILAE), gout data from the FinnGen consortium and a GWAS of clinically defined gout and its subtypes, and UA data from the BioBank Japan (BBJ) and a genome-wide meta-analysis of serum UA levels in Japanese individuals. The inverse-variance weighted (IVW) method served as the primary causal inference approach. To ensure robustness, we complemented this with 3 additional methods: MR-Egger, weighted median, and MR using Robust Adjusted Profile Score (MR-RAPS) - the latter specifically employed to account for potential weak instrument bias due to the limited number of single-nucleotide polymorphisms (SNPs) included in this analysis. RESULTS: Our analysis identified a causal association between genetically predicted gout and an increased risk of epilepsy (odds ratio (OR) = 1.014, 95% confidence interval (95% CI): 1.011-1.017, p < 0.001), generalized epilepsy (OR = 1.009, 95% CI: 1.000-1.018, p = 0.042), and focal epilepsy (OR = 1.044, 95% CI: 1.002-1.088, p = 0.041) in Europeans. In contrast, UA levels showed no significant association with epilepsy or its subtypes in this population. Similarly, neither gout nor UA levels were linked to epilepsy in East Asians. Sensitivity analyses generally supported the robustness of the primary findings. CONCLUSIONS: This MR study provides genetic evidence supporting a potential causal role of gout in increasing the risk of epilepsy, including generalized and focal epilepsy, in European populations. In contrast, genetically predicted UA levels showed no significant association with epilepsy. These findings support a potential role of gout in epilepsy risk and warrant further investigation into the underlying mechanisms.