The Epilepsy Phenome/ Genome Project (EPGP)

描述(由申请人提供)：癫痫是最常见的神经疾病之一，对个人和家庭都有巨大的医学和社会影响。癫痫的治疗方法大多是经验性的，而不是基于对基本机制的了解，因为癫痫发生和癫痫发生的机制知之甚少。癫痫表型组/基因组计划(EPGP)是一个大规模的、全国性的、多机构的合作研究项目，旨在促进我们对最常见的特发性和隐源性癫痫以及症状性癫痫的子集的遗传学基础的了解，即可能与遗传易感性或发育异常有关的癫痫，而不是内源性的获得性因素，如中枢神经系统感染、头部创伤或中风。EPGP的总体战略是收集3750名癫痫患者和3000名对照的详细、高质量的表型信息，并使用最先进的基因组和计算方法来确定遗传变异对以下方面的贡献：1)癫痫表型，2)大脑发育异常，3)使用AEDs治疗的患者的不同治疗反应。EPGP联盟成立于3年前，由15个美国学术机构组成，由行政和科学核心组成。通过规划拨款的资助，该联盟已经规划了招生方案、数据收集方法、分析方法以及开展拟议研究所需的许多基础设施。强大的高通量方法的应用将使我们能够有效地执行本应用程序中描述的大规模基因分型和其他分析。这些研究将使我们能够解决关于最常见形式癫痫背后的潜在基因组机制的关键悬而未决的问题，这些问题还很少被了解，并促进我们对可变药物反应的遗传学的理解。通过NINDS人类遗传学资料库及时共享数据和建立患者细胞系，将极大地便利全国其他癫痫研究人员的工作。重要的是，EPGP直接符合NINDS的高度优先的战略目标之一，如癫痫研究基准的基准B2所规定的：“组织一个全国性的科学家小组，通过开展一个将癫痫患者与特定基因模式联系起来的大型筛查项目，共同寻找可能导致癫痫的基因。”

DESCRIPTION (provided by applicant): Epilepsy is one of the most common neurological disorders and has enormous impact, both medical and social, for the individual as well as for the family. Treatments developed for epilepsy have largely been empirical rather than derived from knowledge of basic mechanisms, because the mechanisms underlying seizure occurrence and epileptogenesis are poorly understood. The Epilepsy Phenome/Genome Project (EPGP) is a large-scale, national, multi-institutional, collaborative research project aimed at advancing our understanding of the genetic basis of the most common forms of idiopathic and cryptogenic epilepsies and a subset of symptomatic epilepsy; i.e. epilepsies that are probably related to genetic predispositions or developmental anomalies rather than endogenous, acquired factors such as CNS infection, head trauma or stroke. The overall strategy of EPGP is to collect detailed, high quality phenotypic information on 3,750 epilepsy patients and 3,000 controls, and to use state-of-the-art genomic and computational methods to identify the contribution of genetic variation to: 1) the epilepsy phenotype, 2) developmental anomalies of the brain, and 3) the varied therapeutic response of patients treated with AEDs. The EPGP Consortium was formed 3 years ago and is comprised of 15 U.S. academic institutions and organized into administrative and scientific cores. Through funding from a planning grant, the Consortium has already planned enrollment protocols, data collection methods, analytical approaches, and much of the infrastructure necessary for carrying out the proposed studies. The application of powerful high-throughput methodologies will permit us to efficiently perform the large- scale genotyping and other analyses described in this application. These studies will allow us to address critical unresolved questions concerning the underlying genomic mechanisms behind the most common forms of epilepsy, which are poorly understood, and to advance our understanding of the genetics of variable drug response. Timely data-sharing and the establishment of patient cell lines through the NINDS Human Genetics Repository will greatly facilitate the work of other epilepsy investigators throughout the country. Importantly, EPGP directly matches one of the high-priority, strategic objectives of NINDS as specified in Benchmark B2 of the Benchmarks for Epilepsy Research: "Organize a national group of scientists to work together in search of genes that might contribute to epilepsy by doing a large screening project that links people with epilepsy to particular gene patterns."