1/4 - The Autism Sequencing Consortium: Autism Gene Discovery in >50,000 Exomes

1/4 - 自闭症测序联盟：在 >50,000 个外显子组中发现自闭症基因

• 批准号: 9217160
• 负责人: Joseph D. Buxbaum
• 金额: $ 54.33万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217160
• 关键词: Alzheimer' s Disease; Architecture; Autistic Disorder; Budgets; Caring; Categories; Cations; Chromatin; Classification; Clinical; Collection; Copy Number Polymorphism; Data; Data Analyses; Development; Diagnosis; Etiology; Family; Foundations; Funding; Genes; Genetic; Genetic Counseling; Genetic Risk; Genetic Variation; Genomic Segment; Genomics; Goals; Grant; Individual; Inherited; Institutes; Intellectual functioning disability; Lead; Methods; Mission; Molecular; Molecular Profiling; Molecular Target; National Human Genome Research Institute; Neurobiology; Neurodevelopmental Disorder; Nucleotides; Outcome; Parents; Pathogenesis; Pathway interactions; Patient Care; Patients; Pharmacology; Prevention; Production; Public Health; Recommendation; Regulation; Research; Resources; Risk; Role; Route; Sampling; Schizophrenia; Sequence Analysis; Site; Statistical Methods; Surface; Symptoms; System; Techniques; United States National Institutes of Health; Variant; Work; autism spectrum disorder; base; case control; clinical practice; clinically significant; cohort; cost; developmental disease; disability; disorder risk; drug development; exome; exome sequencing; gene discovery; genetic variant; genome wide association study; high risk; improved; innovation; insertion/deletion mutation; insight; loss of function mutation; neuropsychiatric disorder; new therapeutic target; novel; novel diagnostics; novel strategies; novel therapeutics; outcome forecast; rare variant; risk variant; spatiotemporal; therapeutic target; transcriptome sequencing; treatment strategy; whole genome

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.

项目摘要/摘要 在过去的十年中，自闭症谱系障碍（ASD）的遗传学取得了出色的进步，但是 只有数百个基因和基因组地区的现代数量被认为与ASD有关 被确定。进步主要来自对罕见遗传变异的研究，尤其是从头变异 包括单个核苷酸变化（SNV），插入/缺失（Indels），拷贝数变化（CNV）和 较大的染色体失衡。 ASD的一部分进展是通过自闭症的努力来实现的 测序联盟（ASC），代表40多个独立组的协调努力 迅速识别ASD风险基因。在这里，我们建议继续进行ASC的工作，在很大程度上是由 来自ASD受试者及其家人的序列数据的分析和分析。 ASC受益于取代 利用资源的利用，包括以广泛研究所为中心 ASC样品的Tute（BI）和全外观测序（WES），由BI的NHGRI中心授予，to 使此更新尽可能低。我们还计划了新的研究途径，例如整合整体 基因组序列（WGS）数据和基于从对普通变体的研究到的思想的基础 了解常见和稀有变体的相互作用以影响风险。通过这项新研究，我们将加速 吃我们的整体目标，即ASD基因的识别，从而支持我们的长期目标 为ASD出现的治疗目标建立基础。我们的理由是确定 基因会议会议对ASD和相关神经发育障碍的重大风险可以构成 了解发病机理的研究以及新型疗法的基础。而且，这样的变体有 就病因诊断，遗传咨询和PA-而言，对患者及其家人的直接影响 tient护理。我们的中心假设是基于过去十年的结果制定的 - 罕见和com- MON变异还助长了ASD风险，但只有某些稀有变体会议会议很大的风险。这 目标将以以下特定目的来实现：1）生产和/或分析30,000的WES 新的ASD受试者，父母和其他控件，总共有50,000多个样本； 2）开发和应用 找到“隐藏”风险变体的方法，3）使用常见和稀有变体研究的结果来描述 这种差异在ASD风险中的相互作用。这项贡献很重要，因为它代表了第一步 了解ASD发病机理的研究以及制定治疗的药物策略 ASD和病因相关的神经发育障碍的核心症状。研究研究 在我们看来，Posed是创新的，因为它使用开创性和新颖的统计方法来识别 风险变体以及整合稀有和常见变化。这是一个新的，实质上不同的ap- 在ASD中发现基因发现的基因发现，该发现与现状显着不同，并提供了手段 实现这些重要目标。