基于全基因组关联的颞叶内侧癫痫内表型的影像遗传学研究

Mesial temporal lobe epilepsy (MTLE) is one kind of complex diseases caused by both genetic and environmental factors. Evidence demonstrates that genetic factors play important roles in MTLE by twin researches, family investigations and population-based epidemiology studies. However, the etiology of MTLE is still unclear. Imaging genetics studies based on genome-wide association study (GWAS) and endophenotype can aid in finding common variations in complex traits or sporadic diseases and identifying susceptible genes related to abnormal brain structures or functions. To date, there are few similar studies focused on MTLE. On the basis of our previous work, the current project intends to identify MTLE-endophenotypes concerning abnormalities in cognitive function, brain structure or function by analyzing cognitive function scales and multi-modal MRI (3D-T1, DTI, fMRI) data for establishing clinical and imaging database based on MTLE-endophenotypes; applying GWAS strategy to analyze association between endophenotype and susceptible SNPs to identify MTLE-related genes or susceptibility loci; and conduct preliminarily study on the underlying mechanism how variants lead to changes in brain structure or function. The proposed study will provide an imaging genetic basis for revealing the mechanism of MTLE and clear guidance for individualized treatment on epilepsy patients.

颞叶内侧癫痫（MTLE）是一类遗传因素和环境因素共同作用的复杂性状疾病，双生子研究、家系研究和群体流行病学调查表明遗传因素在MTLE中扮演了重要角色。基于全基因组关联的内表型的影像遗传学研究可减少临床和遗传异质性，发现散发复杂性状疾病的常见变异，鉴定脑结构和功能相关的易感基因，但在MTLE中尚无研究。本项目组拟利用已有的癫痫临床大数据库，对MTLE患者及其一级亲属进行认知功能评估和多模态磁共振（3D-T1、DTI、fMRI）检测，鉴定MTLE相关的认知功能、脑结构和功能内表型，建立内表型数据库；应用全基因组关联研究策略分析内表型与单核苷酸多态性（SNPs）之间的关联，发现MTLE相关的易感位点或基因；初步探讨基因变异引起的脑结构和功能改变，以揭示颞叶内侧癫痫的影像遗传学机制，为其个体化治疗提供方案。

颞叶内侧癫痫（MTLE）是最常见的癫痫综合征之一，尽管遗传因素在MTLE中扮演重要角色，但MTLE的相关影像遗传学研究尚处于早期阶段。本研究按原计划建立和完善了MTLE患者、无症状兄弟姐妹和健康对照的临床、神经心理量表、多模态影像资料及gDNA数据库，并进行了相关数据分析。结果显示，患者存在脑结构功能网络异常，并与智力、命名、言语流畅性等认知功能障碍相关。进一步探究颞叶癫痫相关的认知和影像学内表型，对患者、无症状兄弟姐妹进行多模态磁共振检测发现，海马体积、表面形态学特征及脑白质损伤可能是颞叶癫痫的内表型，并可作为遗传学研究的潜在靶标。对MTLE患者进行全基因组甲基化分析，鉴定出MTLE诊断及耐药相关CpGs，表明DNA甲基化可作为癫痫诊断与耐药的生物学标记物。进一步以NR4A1基因的甲基化水平作为参考指标进行3D-T1、DTI、fMRI多模态共变分析，发现MTLE外周血中更高的NR4A1甲基化水平可影响脑结构和功能环路，并与癫痫早期发作和严重的认知缺陷相关，部分揭示了MTLE的基因异常与脑结构功能影像改变等内表型关联的影像遗传学机制，为其个体化早期诊断治疗提供了更多的理论依据。