The Autism Sequencing Consortium: Autism Gene Discovery in >50,000 Exomes

项目总结/摘要 然而，在过去的十年里，自闭症谱系障碍（ASD）的遗传学取得了显著的进展， 在被认为与ASD有关的数百个基因和基因组区域中， 被识别。这些进展主要来自于对罕见遗传变异的研究，特别是对新生变异的研究。 突变，包括单核苷酸变异（SNV）、插入/缺失（indel）、拷贝数变异（CNV）和 更大的染色体失衡。ASD的一部分进展来自自闭症患者的努力， 测序联盟（ASC），代表了40多个独立团体的协调努力， 快速识别ASD风险基因。在这里，我们建议继续ASC的工作，主要是通过继续支持， ASD受试者及其家系的序列数据的归纳和分析。ASC受益于实质性的 充分利用各种资源，包括以广泛研究为中心的外显子组聚合联盟（ExAC）， ASC样品的测序（BI）和全外显子组测序（WES），由NHGRI中心资助BI， 使这种更新的成本尽可能低。我们还计划新的研究途径，如整合整体 基因组序列（WGS）数据，并建立在研究常见变异的基础上， 了解常见和罕见变异对风险的影响。通过这项新的研究，我们将加速- 我们的总体目标是确定ASD基因，从而促进我们的长期目标， 为ASD的治疗目标奠定基础。我们的理由是， 对ASD和相关神经发育障碍具有显著风险的基因可以形成 了解发病机制的研究，以及新疗法的基础。此外，这些变体具有 对患者及其家属在病因诊断、遗传咨询和治疗方面的直接影响， tient care.我们的核心假设--根据过去十年的结果制定--是罕见且一致的 mon变异增加了ASD的风险，但只有某些罕见的变异才有实质性的风险。的 目标将通过以下具体目标来实现：1）生产和/或分析30，000个WES 新的ASD受试者、父母和其他对照，总共超过50，000个样本; 2）开发和应用 发现“隐藏”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 ASD风险的这种变化的相互作用。这一贡献意义重大，因为它代表了 研究了解ASD的发病机制和治疗的药理学策略的发展， ASD的核心症状和病因学相关的神经发育障碍。研究专家- 在我们看来，它是创新的，因为它使用了开创性和新颖的统计方法来识别- 风险变异和整合罕见和常见变异。这是一个新的和实质性不同的ap- 探索ASD中的基因发现，这与现状有很大不同，并提供了 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 varia- tion, 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 pro- duction and analysis of sequence data from ASD subjects and their families. The ASC benefits from substan- tial leveraging of resources, including the Exome Aggregation Consortium (ExAC) centered at the Broad Insti- tute (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 accel- erate 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 pa- tient care. Our central hypothesis – formulated based on results over the past decade – is that rare and com- mon 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 treat- ment of core symptoms of ASD and etiologically related neurodevelopmental disorders. The research pro- posed is innovative, in our opinion, because it uses groundbreaking and novel statistical methods for identify- ing risk variants and for integrating rare and common variation. This is a new and substantively different ap- proach to gene discovery in ASD that departs significantly from the status quo and provides the means to achieve these important goals.