The association between epilepsy and COVID-19: analysis based on Mendelian randomization and FUMA

OBJECTIVE: A multitude of observational studies have underscored a substantial comorbidity between COVID-19 and epilepsy. This study was aimed at establishing a conclusive causal link between these two conditions. METHODS: We employed Mendelian randomization (MR) to evaluate the causal link between COVID-19 and epilepsy, as well as its focal and generalized subtypes. The GWAS for epilepsy and its subtypes database were abstracted from both FinnGen consortium and ILAE. Additionally, we leveraged functional mapping and annotation (FUMA) to integrate information from genome-wide association studies (GWAS) results. RESULTS: The MR analyses revealed that genetic liability to COVID-19 infection conferred a causal effect on epilepsy [FinnGen: OR: 1.5306; 95% confidence interval (CI): 1.1676–2.0062, P(FDR) (false discovery rate) = 0.0076; ILAE: OR: 1.3440; 95% CI: 1.0235–1.7649, P(FDR) = 0.0429], and generalized epilepsy (FinnGen: OR: 2.1155; 95% CI: 1.1734–3.8139, P(FDR) = 0.0327; ILAE: OR: 1.1245; 95% CI: 1.0444–1.2108, P(FDR) = 0.0114). Genetic liability to COVID-19 hospitalization conferred a causal effect on epilepsy (FinnGen: OR: 1.0934; 95% CI: 1.0097–1.1841, P(FDR) = 0.0422; ILAE: OR: 1.7381; 95% CI: 1.0467–2.8862, P(FDR) = 0.0451), focal epilepsy (ILAE: OR: 1.7549; 95% CI: 1.1063–2.7838, P(FDR) = 0.0338), and generalized epilepsy (ILAE: OR: 1.1827; 95% CI: 1.0215–1.3693, P(FDR) = 0.0406). Genetic liability to COVID-19 severity conferred a causal effect on epilepsy (FinnGen consortium: OR: 1.2454; 95% CI: 1.0850–1.4295, P(FDR) = 0.0162; ILAE: OR: 1.2724; 95% CI: 1.0347–1.5647, P(FDR) = 0.0403), focal epilepsy (FinnGen: OR: 1.6818; 95% CI: 1.1478–2.4642, P(FDR) = 0.0231; ILAE: OR: 1.6598; 95% CI: 1.2572–2.1914, P(FDR) = 0.0054), and generalized epilepsy (FinnGen: OR: 1.1486; 95% CI: 1.0274–1.2842, P(FDR) = 0.0335; ILAE: OR: 1.0439; 95% CI: 1.0159–1.0728, P(FDR) = 0.0086). In contrast, no causal linkage of epilepsy on COVID-19 was observed. Further, FUMA analysis identified six overlapping genes, including SMEK2, PNPT1, EFEMP1, CCDC85A, VRK2, and BCL11A, shared between COVID-19 and epilepsy. Tissue-specific expression analyses revealed that the disease-gene associations of COVID-19 were significantly enriched in lung, ovary, and spleen tissue compartments, while being significantly enriched in brain tissue for epilepsy. CONCLUSION: Our study demonstrates that COVID-19 can be a contributing factor to epilepsy, but we found no evidence that epilepsy contributes to COVID-19.