Kim Joonho, Cho Soomi, Jeong Kyoung Hoon, Ha Woo-Seok, Kim Kyung Min, Chu Min Kyung, Lee Ji Hyun, Kim Sangwoo, Kim Won-Joo
Department of Neurology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Department of Biomedical Systems Informatics, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
J Clin Med. 2025 May 29;14(11):3810. doi: 10.3390/jcm14113810.
: Hippocampal sclerosis (HS) is a hallmark of mesial temporal lobe epilepsy (MTLE). However, genetic studies on MTLE patients with HS (MTLE-HS) remain limited, especially in East Asian populations. This study aimed to identify genetic variants associated with MTLE-HS and elucidate their biological relevance through integrative genomic and transcriptomic analyses. : We conducted a genome-wide association study (GWAS) on 157 Korean epilepsy patients, including 52 MTLE-HS subjects and 105 non-acquired focal epilepsy individuals without HS as controls. The splicing and expression quantitative trait locus (sQTL and eQTL, respectively) effects of significant variants were analyzed using GTEx datasets. Transcriptomic data from the hippocampi of MTLE-HS subjects and an epilepsy mouse model were examined to assess expression. Gene correlation enrichment analysis was performed to investigate potential associations with epilepsy-related phenotypes. : The GWAS identified rs6924849, located downstream of , as significantly associated with MTLE-HS. The sQTL analysis revealed that rs6924849 induces abnormal splicing in hippocampal tissue. Transcriptomic analyses showed reduced expression in MTLE-HS hippocampi, while mice with pilocarpine-induced epilepsy exhibited a transient increase in expression during the acute phase post-status epilepticus. Gene correlation enrichment analyses linked to seizure-related phenotypes in both humans and mice. : This study identifies rs6924849 as a novel genetic variant associated with MTLE-HS in an East Asian population. The dysfunctional splicing and altered expression of may contribute to the neuronal loss characteristic of HS, as regulates apoptosis. These findings emphasize the potential role of in MTLE-HS pathogenesis from genomic and transcriptomic perspectives.
海马硬化（HS）是内侧颞叶癫痫（MTLE）的一个标志。然而，对患有HS的MTLE患者（MTLE-HS）的遗传学研究仍然有限，尤其是在东亚人群中。本研究旨在通过综合基因组和转录组分析，鉴定与MTLE-HS相关的基因变异，并阐明其生物学相关性。
我们对157名韩国癫痫患者进行了全基因组关联研究（GWAS），其中包括52名MTLE-HS受试者和105名无HS的非后天性局灶性癫痫个体作为对照。使用GTEx数据集分析了显著变异的剪接和表达数量性状位点（分别为sQTL和eQTL）效应。检查了MTLE-HS受试者海马体和癫痫小鼠模型的转录组数据，以评估表达情况。进行基因相关性富集分析，以研究与癫痫相关表型的潜在关联。
GWAS确定位于[具体基因名称]下游的rs6924849与MTLE-HS显著相关。sQTL分析表明，rs6924849在海马组织中诱导异常剪接。转录组分析显示，MTLE-HS海马体中的[具体基因名称]表达降低，而毛果芸香碱诱导的癫痫小鼠在癫痫持续状态后的急性期[具体基因名称]表达短暂增加。基因相关性富集分析将[具体基因名称]与人类和小鼠的癫痫发作相关表型联系起来。
本研究确定rs6924849是东亚人群中与MTLE-HS相关的一个新的基因变异。由于[具体基因名称]调节细胞凋亡，其剪接功能失调和表达改变可能导致HS特有的神经元丢失。这些发现从基因组和转录组角度强调了[具体基因名称]在MTLE-HS发病机制中的潜在作用。
