3/4 - The Autism Sequencing Consortium: Autism Gene Discovery in >50,000 Exomes

项目摘要/摘要 然而，在过去的十年里，自闭症谱系障碍(Asd)的遗传学研究取得了显著进展。 在被认为与ASD有关的数百个基因和基因组区域中，只有中等数量的基因和基因组区域 已被确认身份。进展主要来自对罕见遗传变异的研究，特别是从头变异，包括单核苷酸变异(SNV)、插入/缺失(INDELs)、拷贝数变异(CNV)和 更大的染色体失衡。自闭症的部分进展来自自闭症患者的努力 测序联盟(ASC)，它代表了40多个独立组织的协调努力，以 快速识别ASD风险基因。在这里，我们建议继续ASC的工作，主要是通过继续产生和分析ASD受试者及其家族的序列数据。ASC受益于资源的大量利用，包括以博德研究所(BI)为中心的Exome聚合联盟(ExAC)和ASC样本的完整外显子组测序(WES)，并得到NHGRI中心对BI的拨款支持，以 使此次续订的成本尽可能低。我们还规划了新的研究途径，例如整合整个 基因组序列(WGS)数据，并建立在对常见变异的研究中产生的想法 了解常见变量和罕见变量对风险的相互影响。通过这项新的研究，我们将加快我们的总体目标，即识别ASD基因，从而促进我们的长期目标 建立ASD治疗靶点出现的基础。我们的理论基础是，确定 导致自闭症和相关神经发育障碍的显著风险的基因可形成 研究以了解发病机制，以及新疗法的基础。此外，这些变种具有 在病原学诊断、遗传咨询和患者护理方面对患者及其家人的直接影响。我们根据过去十年的研究结果提出的中心假设是，罕见和常见的变异增加了ASD的风险，但只有某些罕见的变异才会带来实质性的风险。这个 将实现以下具体目标：1)产生和/或分析30,000个WE 新的自闭症受试者、父母和其他对照，总共超过5万个样本；2)开发和应用 寻找“隐藏的”风险变异的方法，以及，3)使用常见和罕见变异研究的结果来描述 这种变异在ASD风险中的相互作用。这一贡献意义重大，因为它代表着 研究了解ASD的发病机制，并开发治疗ASD核心症状和病因学相关神经发育障碍的药理学策略。我们认为，提出的研究是创新的，因为它使用了突破性的和新颖的统计方法来识别风险变量，并整合了罕见和常见的变量。这是一种新的和本质上不同的ASD基因发现方法，它显著地偏离了现状，并提供了以下方法 实现这些重要目标。

Project Summary/Abstract The past decade has seen outstanding advances in the genetics of autism spectrum disorder (ASD), however only a moderate number of the hundreds of genes and genomic regions thought to be involved in ASD have been identified. Advances have come largely from the study of rare genetic variants, especially de novo variation, including single nucleotide variation (SNV), insertion/deletions (indels), copy number variation (CNV), and larger chromosomal imbalances. A portion of the progress for ASD has come through the efforts of the Autism Sequencing Consortium (ASC), which represents a coordinated effort by more than 40 independent groups to rapidly identify ASD risk genes. Here we propose to continue the work of the ASC, largely by continued production and analysis of sequence data from ASD subjects and their families. The ASC benefits from substantial leveraging of resources, including the Exome Aggregation Consortium (ExAC) centered at the Broad Institute (BI) and whole-exome sequencing (WES) of ASC samples, supported by an NHGRI Center Grant to BI, to make this renewal as low cost as possible. We also plan new avenues of research, such as integrating whole genome sequence (WGS) data and building on ideas that have emerged from the study of common variants to understand the interplay of common and rare variants to impact risk. Through this new research we will accelerate our overall objective, which is the identification of ASD genes, thereby facilitating our long-term goal of building the foundation from which therapeutic targets for ASD emerge. Our rationale is that the identification of genes conferring significant risk to ASD and associated neurodevelopmental disorders can form the basis of studies to understand pathogenesis, as well as the basis for novel therapies. Moreover, such variants have direct implications for patients and their families in terms of etiological diagnosis, genetic counseling and patient care. Our central hypothesis – formulated based on results over the past decade – is that rare and common variation contributes additively to risk for ASD, but only certain rare variants confer substantial risk. The objectives will be accomplished with the following Specific Aims: 1) Produce and/or analyze WES of 30,000 new ASD subjects, parents and other controls, for a total of more than 50,000 samples; 2) Develop and apply approaches to find “hidden” risk variants, and, 3) Use results from common and rare variant studies to describe the interplay of such variation in ASD risk. This contribution is significant because it represents the first step in research to understand pathogenesis of ASD and to the development of pharmacological strategies for treatment of core symptoms of ASD and etiologically related neurodevelopmental disorders. The research proposed is innovative, in our opinion, because it uses groundbreaking and novel statistical methods for identifying risk variants and for integrating rare and common variation. This is a new and substantively different approach to gene discovery in ASD that departs significantly from the status quo and provides the means to achieve these important goals.