Complex genetics of idiopathic epilepsies

癫痫是一种常见的神经系统疾病，影响0.5%-1%的人口。特发性全面性癫痫(IGE)和罗兰迪克癫痫(RE)是最常见的特发性综合征，主要是遗传性的，代表了具有复杂遗传的常见疾病的原型。已在单基因免疫球蛋白E中发现罕见的突变(主要发生在离子通道中)，或在免疫球蛋白E和RE中作为危险因素。在大约3%的IGE患者中，已经发现了微缺失，但绝大多数易患这两种疾病的遗传风险因素仍有待确定。特发性癫痫复杂遗传学联合会(CoGIE)的目标是揭示IGE和RE的遗传基础和病理生理学。该联盟的目标是在全基因组的基础上识别常见和罕见的与疾病相关的遗传变异，并确定已识别的变异的功能作用。CoGIE利用由临床医生、遗传学家、生物统计学家、生理学家和神经解剖学家组成的成熟而独特的跨学科研究网络。CoGIE将扩大CoGIE合作伙伴和欧洲Epicure项目内其他合作者已经收集的具有良好特征的IGE和RE患者的最大队列。通过结合现代基因技术，包括下一代测序、全基因组关联研究、拷贝数变异分析和高通量SNP基因分型，我们将识别和验证IGE和RE的遗传危险因素。随后，将对所产生的遗传数据进行全面的生物统计学分析，以探索免疫球蛋白E和RE的共同病因。选定的遗传变异将利用自动化和传统的电生理学技术和神经元表达进行功能表征，神经解剖学研究将确定受影响基因的神经元表达模式。我们期待我们的研究将具有揭示常见特发性癫痫综合征新的病理生理途径的力量和新颖性。

Epilepsy is a common neurological disorder affecting 0.5-1% of the population. Idiopathic generalized epilepsy (IGE) and Rolandic epilepsy (RE), the most common idiopathic syndromes, are largely genetic and represent prototypes for common diseases with complex inheritance. Rare mutations (mainly in ion channels) have been identified in monogenic IGE or as risk factors in IGE and RE. In approximately 3% of IGE patients, microdeletions have been identified but the vast majority of genetic risk factors predisposing to both diseases remains to be identified. The objective of the ‘Complex Genetics of Idiopathic Epilepsies’ consortium (CoGIE) is to unravel the genetic basis and pathophysiology of IGE and RE. The consortium aims to identify both common and rare disease-relevant genetic variations on a genome-wide basis and to determine the functional role of identified variants. CoGIE exploits an established and unique interdisciplinary research network of clinicians, geneticists, biostatisticians, physiologists and neuroanatomists.CoGIE will expand the largest cohorts of well-characterized IGE and RE patients already collected by CoGIE partners and other collaborators within the European EPICURE project. By using a combination of modern genetic techniques, including next generation sequencing, genome-wide association studies, copy number variation analysis, and high-throughput SNP genotyping, we will identify and validate the genetic risk factors for IGE and RE. Subsequently, comprehensive biostatistical analysis of the genetic data generated will be applied to explore the common etiological factors underlying IGE and RE. Selected genetic variants will be characterized functionally using automated and conventional electrophysiological tech-niques and expression in neurons, and neuroanatomical studies will determine the neuronal expression patterns of affected genes. We anticipate that our studies will have the power and novelty to reveal new pathophysiological pathways of common idiopathic epilepsy syndromes.