3/4 - The Autism Sequencing Consortium: Autism gene discovery in >20,000 exomes

3/4 - 自闭症测序联盟：在超过 20,000 个外显子组中发现自闭症基因

• 批准号: 8478295
• 负责人: BERNIE DEVLIN
• 金额: $ 27.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478295
• 关键词: Accounting; Architecture; Autistic Disorder; Bioinformatics; Biological; Budgets; Communication; Copy Number Polymorphism; Data; Data Analyses; Data Set; Development; Diagnosis; Disease; Epilepsy; Family; Genes; Genetic; Genetic Counseling; Genetic Risk; Genome; Genomics; Goals; Hereditary Disease; Individual; Inherited; Lead; Link; Medical Genetics; Methods; Mission; Modeling; Molecular; Molecular Target; National Human Genome Research Institute; Neurobiology; Neurodevelopmental Disorder; Nucleotides; Outcome; Parents; Pathogenesis; Pathway interactions; Patient Care; Patients; Prevention; Public Health; Publications; Recommendation; Recurrence; Research; Research Infrastructure; Resources; Risk; Route; Sampling; Schizophrenia; Site; Statistical Methods; Symptoms; Syndrome; System; Techniques; Translating; United States National Institutes of Health; Update; Variant; autism spectrum disorder; base; clinical practice; clinically significant; data sharing; developmental disease; disability; disorder risk; drug development; drug discovery; exome; exome sequencing; gene discovery; genetic variant; genome sequencing; high risk; improved; innovation; insight; meetings; next generation sequencing; novel; novel diagnostics; novel therapeutics; programs; public health relevance; repository; risk sharing; risk variant; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): While there has been great progress in understanding the genomic architecture of autism, only a moderate number of the hundreds of genes and genomic regions thought to be involved in ASD have been identified. Next-generation sequencing (NGS) has proven its utility to rapidly identify variants underlying ASD, and this approach is being carried out in ca. 6,000 independent ASD samples through multiple studies. There is an urgent need to develop a framework to integrate and expand these current studies, and to jointly analyze emerging data to maximize the identification of valid ASD loci, because validated risk variants present opportunities for genetic counseling, understanding pathogenesis, and drug development. The Autism Sequencing Consortium (ASC) represents a coordinated effort by more than 20 independent groups to rapidly identify and validate ASD risk genes, which represent lead targets for neurobiological analyses and drug discovery. The long-term goal of the ASC is to make use of genetics to identify therapeutic targets in ASD, while contributing to translating such research findings to clinical practice. The overall objective of tis proposal is to rapidly identify ASD genes representing lead targets for high impact neurobiological studies and drug discovery. Our central hypothesis - formulated based on data with SNV, indels, and CNV, as well as review of medical genetic conditions in ASD and targeted sequencing in ASD - is that multiple independent rare variants account for a very significant proportion of risk to ASD. Our rationale for this proposal is that the identification of genetic variants conferring high-risk risk to ASD and associated neurodevelopmental disorders can form the bases of studies to understand pathogenesis as well as the bases for novel therapies. Moreover, such variants have direct implications for patients and their families in terms of etiological diagnosis, genetic counseling and patient care. These objectives will be accomplished with the following Specific Aims: 1) Maintain the infrastructure to support the ASC objectives; 2) Deploy pipelines for data cleaning and harmonization and variant calling; 3) Implement novel statistical methods for identifying ASD-associated genes; and, 4) Carry out whole-exome sequencing of 3,000 ASD subjects and parents. 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 in this application is innovative, in our opinion, because it involves an entirely new model of sharing data before publication, uses state-of-the-art methods for calling diverse types of variants in NGS data, incorporates novel methods for updating variant calling and sharing data, and includes highly innovative statistical methods to identify risk loci. 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.

描述（由申请人提供）：虽然在理解自闭症的基因组结构方面取得了长足的进步，但仅确定了被认为涉及ASD的数百个基因和基因组区域中的中等数量。下一代测序（NGS）已证明其效用是快速识别ASD基础的变体，并且该方法正在CA中进行。通过多项研究，有6,000个独立的ASD样品。迫切需要开发一个框架来整合和扩展这些当前的研究，并共同分析新兴数据以最大程度地识别有效的ASD基因座，因为经过验证的风险变体为遗传咨询，理解发病机理和药物发育提供了机会。自闭症测序联盟（ASC）代表了20多个独立组的协调努力，以迅速识别和验证ASD风险基因，这代表了神经生物学分析和药物发现的主要靶标。 ASC的长期目标是利用遗传学来识别ASD中的治疗靶标，同时将这种研究结果转化为临床实践。提案的总体目标是迅速识别代表高影响神经生物学研究和药物发现的铅靶标的ASD基因。我们的中心假设基于使用SNV，Indels和CNV的数据制定，以及对ASD中ASD和靶向测序中的医学遗传条件的审查 - 多个独立的稀有变体占ASD风险的很大比例。我们对该提案的理由是，鉴定遗传变异体给ASD和相关的神经发育疾病赋予高危风险的遗传变异可以构成研究的基础，以理解发病机理以及新型疗法的基础。此外，这种变体在病因诊断，遗传咨询和患者护理方面对患者及其家人具有直接影响。这些目标将通过以下特定目的实现：1）维护支持ASC目标的基础架构； 2）部署管道来清洁和协调和变体调用； 3）实施新的统计方法来识别与ASD相关的基因；以及，4）对3,000名ASD主题和父母进行全外观测序。这项贡献很重要，因为它代表了了解ASD的发病机理的第一步，以及用于治疗ASD和病因与病因相关的神经发育疾病的药理策略的发展。在我们看来，在本应用程序中提出的研究具有创新性，因为它涉及到出版前共享数据的全新模型，它使用最先进的方法来呼叫NGS数据中的多种类型的变体，并结合了更新变体呼叫和共享数据的新方法，并包括高度创新的统计方法来识别风险位置。这是ASD中一种新的且实质性的基因发现方法，它与现状显着背道而驰，并提供了实现这些重要目标的手段。