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

描述（由申请人提供）：虽然在了解自闭症基因组结构方面已经取得了很大进展，但被认为与自闭症相关的数百个基因和基因组区域中仅确定了其中的一小部分。新一代测序 (NGS) 已证明其可快速识别自闭症谱系障碍 (ASD) 变异的实用性，并且该方法正在大约 2019 年实施。通过多项研究获得 6,000 个独立的 ASD 样本。迫切需要开发一个框架来整合和扩展这些当前的研究，并共同分析新出现的数据，以最大限度地识别有效的 ASD 位点，因为经过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 多个独立团体的协调努力，旨在快速识别和验证 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，这些基因代表高影响力神经生物学研究和药物发现的主要目标。我们的中心假设是基于 SNV、indels 和 CNV 数据以及对 ASD 医学遗传状况和 ASD 靶向测序的回顾而制定的，即多种独立的罕见变异在 ASD 风险中占非常大的比例。我们提出这一建议的理由是，识别导致自闭症谱系障碍和相关神经发育障碍高风险的遗传变异可以构成了解发病机制的研究基础以及新疗法的基础。此外，此类变异对患者及其家人的病因诊断、遗传咨询和患者护理具有直接影响。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、协调和变体调用的管道； 3）实施新的统计方法来识别 ASD 相关基因； 4) 对 3,000 名 ASD 受试者及其父母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 发病机制和开发治疗 ASD 核心症状和病因相关神经发育障碍的药理学策略的第一步。我们认为，该申请中提出的研究具有创新性，因为它涉及在发表前共享数据的全新模型，使用最先进的方法来调用NGS数据中的不同类型的变异，结合了更新变异调用和共享数据的新颖方法，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、本质上不同的 ASD 基因发现方法，与现状显着不同，并提供了实现这些重要目标的方法。

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.