Causal association between epilepsy and its DNA methylation profile and atrial fibrillation

Abstract

Background: The "epileptic heart" concept is emerging, but the causal relationship between epilepsy and atrial fibrillation (AF) remains unclarified.

Objective: This study explores the genetic correlations and bidirectional causality between various epilepsy phenotypes and AF.

Methods: Genome-wide association study (GWAS) statistics for 10 epilepsy subtypes (29,944 cases, 52,538 controls) and AF (60,620 cases, 970,216 controls) were sourced from the International League Against Epilepsy (ILAE) and HGRI-EBI Catalog-GWAS, respectively. Linkage disequilibrium score regression (LDSC) and genome-wide Mendelian randomization (MR) evaluated genetic correlations and bidirectional causal relationships. Epilepsy-related DNA methylation data (N = ∼800) from Epigenome-Wide Association Study (EWAS) catalog were analyzed to identify causal CpG sites influencing risk of AF through epigenetic MR.

Results: LDSC revealed significant genetic correlations between 4 epilepsy subtypes and AF (correlation coefficient: rg from 0.116 to 0.241). Forward MR suggested a significant causal effect of focal epilepsy with hippocampal sclerosis (focal epilepsy [FE] with hippocampal sclerosis [HS]) on risk of AF (inverse variance weighting [IVW] and Mendelian randomized pleiotropy residual sum and outlier [MR-PRESSO]: odds ratio [OR] = 1.046, P ≤ .004), with results robust against heterogeneity, horizontal pleiotropy, and outliers. Epigenetic MR indicated that lower methylation at cg06222062 (OR = 0.994, P = 3.16E-04) mapped to PLA2G5 and cg08461451 mapped to SPPL2B gene (OR = 0.954, P = 1.19E-03), and higher cg10541930 in the C10orf143 promoter (OR = 1.043, P = 4.18E-22) increases risk of AF. Sensitivity analyses affirmed no pleiotropic bias.

Conclusion: FE with HS significantly increases AF risk, highlighting the natural neural-cardiac connection and the need for cardiac monitoring in patients with epilepsy. Specific methylated CpG sites may serve as biomarkers and preventive targets for AF susceptibility.

Keywords: Atrial fibrillation; DNA methylation; Epilepsy; Genetic association; Mendelian randomization.