2/5-Elucidating the Genetic Architecture of Autism by Deep Genomic Sequencing

描述（由申请人提供）：本合作申请是为了响应RFA MH-09-171而提交的。自闭症的根本原因仍然未知，限制了理解疾病异质性，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中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，但传统的努力，以确定这种惊人的遗传性的遗传基础已经遇到了非常有限的成功，因此提供了有限的洞察疾病生物学。我们在这里提议在专家大规模测序中心（在贝勒医学院和麻省理工学院和哈佛的布罗德研究所）和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汇集在一起）之间建立前所未有的伙伴关系。这些小组将共同努力，利用DNA测序技术的巨大新进展来揭示自闭症的遗传结构，首先通过详细检查先前遗传研究所涉及的1000个基因或假定为功能相关的基因，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含有易患自闭症的个体或罕见DNA变异的集合，从而将抽象的遗传性转化为疾病发病机制的可靠生物学线索，可以在分子水平上进行研究并进行治疗。这些努力及其后续行动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储存库提供表型数据，这将成为自闭症遗传学研究的基石。 公共卫生相关性：我们建议专家大规模测序中心和研究实验室的合作网络之间的合作伙伴关系，专注于自闭症的遗传学，利用新的高通量基因组测序，以发现自闭症的显着遗传性的特定基因。如果不了解易患疾病的特定基因和DNA变异，我们就缺乏了解疾病生物学过程的基本起点。通过结合大量的、特征良好的患者样本、经验丰富的DNA测序团队以及协作的专家分析和随访网络，这项研究将为疾病生物学提供新的见解，并将揭示构成治疗开发高优先级靶点的基因和途径。

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. PUBLIC HEALTH RELEVANCE: We propose a partnership between expert large-scale sequencing centers and a collaborative network of research labs focused on the genetics of autism to utilize novel high-throughput genome sequencing to discover specific genes underlying the significant heritability of autism. Without knowledge of the specific genes and DNA variants that predispose to disease, we lack the basic starting point with which we might understand the biological processes of disease. By combining large, well-characterized patient samples, experienced DNA sequencing teams and a collaborative, expert analysis and follow-up network, this study will provide novel insight into disease biology and will expose genes and pathways that constitute high priority targets for therapeutic development.