4/5-Elucidating the Genetic Architecture of Autism by Deep Genomic Sequencing

描述（由申请人提供）：此协作申请是根据RFA MH-09-171提交的。自闭症的根本原因仍然未知，这限制了了解疾病异质性、诊断病例以及预防和治疗疾病的努力。流行病学研究结果一再明确地确定，DNA的遗传变异在自闭症和自闭症谱系障碍的病因学中起着重要作用，然而，迄今为止，识别这种惊人遗传性的遗传基础的传统努力取得了非常有限的成功，因此对疾病生物学的了解有限。在此，我们提议在大规模的专家测序中心（贝勒医学院、麻省理工学院和哈佛大学的博德研究所）和一个专注于自闭症遗传学的研究实验室合作网络（由自闭症基因组计划和自闭症联盟联合起来）之间建立一个前所未有的伙伴关系。这些小组将共同努力，利用DNA测序技术的新进展来揭示自闭症的遗传结构，首先通过对先前基因研究中涉及的1000个基因的详细检查，或者假设与功能相关，然后，随着技术的不断进步，通过无偏见的全基因组测序。其目标是最终确定哪些基因携带个体或罕见的DNA变异，使其易患自闭症，从而将抽象的遗传能力转化为疾病发病机制的坚实生物学线索，从而可以进行分子研究和治疗。这些努力及其后续工作，将在自闭症研究小组收集的数千个自闭症家庭中进行，并向NIMH知识库提供表型数据，将形成自闭症基因研究的基石。

DESCRIPTION (provided by applicant): This collaborative application is submitted in response to RFA MH-09-171. The root causes of autism remain unknown, limiting efforts to understand disease heterogeneity, diagnose cases, and prevent and treat disease. Epidemiological findings have repeatedly and unequivocally determined that heritable variation in DNA plays a substantial role in the etiology of autism and autism spectrum disorders, yet traditional efforts to identify the genetic basis of this striking heritability have met with very limited success to date and have therefore provided limited insight into disease biology. We propose here an unprecedented partnership between expert large- scale sequencing centers (at the Baylor College of Medicine and the Broad Institute of MIT and Harvard) and a collaborative network of research labs focused on the genetics of autism (brought together by the Autism Genome Project and the Autism Consortium). These groups will work together to utilize dramatic new advances in DNA sequencing technology to reveal the genetic architecture of autism, first through a detailed examination of 1000 genes implicated by previous genetic studies or postulated to be functionally relevant, and later, as the technology continues to advance, through unbiased whole-genome sequencing. The goal is to conclusively identify which genes harbor individual or collections of rare DNA variants that predispose to autism, and thus translate the abstract heritability into solid biological clues to disease pathogenesis that can be studied molecularly and approached therapeutically. These efforts and their follow-up, which will be performed on thousands of autism families collected by the autism research groups and being provided with phenotype data to NIMH repositories, will form the cornerstone of autism genetic research going forward.