癫痫与其DNA甲基化谱及心房颤动之间的因果关联。

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

作者信息

Zheng Zequn, Chen Haohao, Chen Yanbin, Tan Xuerui

机构信息

Department of Cardiology, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China; Clinical Medical Research Center, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China; Human Phenome institute of SUMC, Guangdong Engineering Research Center of Human Phenome, chemistry and Chemical Engineering Guangdong Laboratory, Shantou, Guangdong, China.

Department of Pharmacy, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.

出版信息

Heart Rhythm. 2024 Sep 12. doi: 10.1016/j.hrthm.2024.09.008.

DOI:10.1016/j.hrthm.2024.09.008

PMID:39260664

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.

摘要

背景

“癫痫性心脏”的概念正在兴起，但癫痫与心房颤动（AF）之间的因果关系仍不明确。

目的

本研究探讨各种癫痫表型与AF之间的遗传相关性和双向因果关系。

方法

10种癫痫亚型（29944例患者，52538例对照）和AF（60620例患者，970216例对照）的全基因组关联研究（GWAS）统计数据分别来自国际抗癫痫联盟（ILAE）和HGRI-EBI目录-GWAS。连锁不平衡评分回归（LDSC）和全基因组孟德尔随机化（MR）评估遗传相关性和双向因果关系。分析来自表观基因组范围关联研究（EWAS）目录的癫痫相关DNA甲基化数据（N =约800），以通过表观遗传MR识别影响AF风险的因果CpG位点。

结果

LDSC揭示了4种癫痫亚型与AF之间存在显著的遗传相关性（相关系数：rg为0.116至0.241）。正向MR表明，伴有海马硬化的局灶性癫痫（FE伴HS）对AF风险有显著因果效应（逆方差加权[IVW]和孟德尔随机化多效性残差和异常值[MR-PRESSO]：比值比[OR]=1.046，P≤.004），结果对异质性、水平多效性和异常值具有稳健性。表观遗传MR表明，映射到PLA2G5的cg06222062处较低甲基化（OR = 0.994，P = 3.16E-04）和映射到SPPL2B基因的cg08461451（OR = 0.954, P = 1.19E-03），以及C10orf143启动子中较高的cg10541930（OR = 1.043, P = 4.18E-22）会增加AF风险。敏感性分析确认无多效性偏差。