4/4 The Autism Sequencing Consortium: Autism gene discovery in the >20,000 exomes (supplement)

描述（由申请人提供）：虽然在了解自闭症的基因组结构方面取得了很大进展，但只有数百个被认为与自闭症有关的基因和基因组区域中的中等数量被确定。新一代测序（NGS）已经证明了它在快速识别ASD变异方面的实用性，这种方法正在通过多项研究在大约6000个独立的ASD样本中进行。目前迫切需要建立一个框架来整合和扩展这些现有的研究，并共同分析新出现的数据，以最大限度地确定有效的ASD位点，因为验证的风险变异为遗传咨询、了解发病机制和药物开发提供了机会。自闭症测序联盟（ASC）代表了20多个独立小组的协调努力，以快速识别和验证ASD风险基因，这些基因代表了神经生物学分析和药物发现的主要目标。ASC的长期目标是利用遗传学来确定ASD的治疗靶点，同时有助于将这些研究成果转化为临床实践。该提案的总体目标是快速识别ASD基因，代表高影响神经生物学研究和药物发现的主要目标。我们的中心假设——基于SNV、indels和CNV的数据，以及对ASD医学遗传条件和ASD靶向测序的回顾——是多个独立的罕见变异在ASD风险中所占的比例非常大。我们提出这一建议的基本原理是，识别赋予ASD和相关神经发育障碍高风险的遗传变异可以为了解发病机制和新疗法的研究奠定基础。此外，这些变异在病因诊断、遗传咨询和患者护理方面对患者及其家属有直接影响。这些目标将通过以下具体目标来实现：1)维护基础设施以支持ASC目标；2)部署数据清理协调和变量调用管道；3)采用新的统计方法鉴定自闭症相关基因；4)对3000名ASD受试者及家长进行全外显子组测序。这一贡献意义重大，因为它代表了了解ASD发病机制的研究的第一步，以及ASD核心症状和病因相关神经发育障碍的药理学治疗策略的发展。在我们看来，本申请中提出的研究是创新的，因为它涉及一种全新的在发表前共享数据的模型，使用最先进的方法来调用NGS数据中的不同类型的变体，采用新颖的方法来更新变体调用和共享数据，并包括高度创新的统计方法来识别风险位点。这是一种新的、实质上不同的方法来发现ASD的基因，它与现状有很大的不同，并为实现这些重要目标提供了手段。

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.