TMEM14A Gene Affects Hippocampal Sclerosis in Mesial Temporal Lobe Epilepsy

<b>Background</b>: 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. <b>Methods</b>: 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 <i>TMEM14A</i> expression. Gene correlation enrichment analysis was performed to investigate potential associations with epilepsy-related phenotypes. <b>Results</b>: The GWAS identified rs6924849, located downstream of <i>TMEM14A</i>, as significantly associated with MTLE-HS. The sQTL analysis revealed that rs6924849 induces abnormal <i>TMEM14A</i> splicing in hippocampal tissue. Transcriptomic analyses showed reduced <i>TMEM14A</i> expression in MTLE-HS hippocampi, while mice with pilocarpine-induced epilepsy exhibited a transient increase in <i>TMEM14A</i> expression during the acute phase post-status epilepticus. Gene correlation enrichment analyses linked <i>TMEM14A</i> to seizure-related phenotypes in both humans and mice. <b>Conclusions</b>: 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 <i>TMEM14A</i> may contribute to the neuronal loss characteristic of HS, as <i>TMEM14A</i> regulates apoptosis. These findings emphasize the potential role of <i>TMEM14A</i> in MTLE-HS pathogenesis from genomic and transcriptomic perspectives.