3/4 - The Autism Sequencing Consortium: Autism Gene Discovery in >50,000 Exomes

3/4 - 自闭症测序联盟：在 >50,000 个外显子组中发现自闭症基因

基本信息

批准号：
10115120
负责人：
BERNIE DEVLIN
金额：
$ 39.2万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-05 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115120
关键词：
Alzheimer&apos s Disease Budgets Categories 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 Target National Human Genome Research Institute Neurobiology Neurodevelopmental Disorder Nucleotides Outcome Parents Pathogenesis Pathway interactions Patient Care Patients Pharmacology Prevention Production Prognosis 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 architecture genetic variant genome wide association study high risk improved individuals with autism spectrum disorder innovation insertion/deletion mutation insight loss of function mutation neuropsychiatric disorder new therapeutic target novel novel diagnostics novel strategies novel therapeutics rare variant risk variant spatiotemporal therapeutic target transcriptome sequencing treatment strategy whole genome

项目摘要

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 variation, 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 production and analysis of sequence data from ASD subjects and their families. The ASC benefits from substantial leveraging of resources, including the Exome Aggregation Consortium (ExAC) centered at the Broad Institute (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 accelerate 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 patient care. Our central hypothesis – formulated based on results over the past decade – is that rare and common 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 treatment of core symptoms of ASD and etiologically related neurodevelopmental disorders. The research proposed is innovative, in our opinion, because it uses groundbreaking and novel statistical methods for identifying risk variants and for integrating rare and common variation. 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.

项目概要/摘要然而，在过去的十年里，自闭症谱系障碍 (ASD) 的遗传学取得了显着的进展数百个被认为与自闭症谱系障碍有关的基因和基因组区域中，只有中等数量的基因和基因组区域具有进展主要来自对罕见遗传变异的研究，特别是从头变异，包括单核苷酸变异（SNV）、插入/缺失（indels）、拷贝数变异（CNV）和自闭症谱系障碍的部分进展归功于自闭症患者的努力。测序联盟 (ASC)，代表 40 多个独立团体的协调努力，在此，我们建议继续 ASD 的工作，主要是通过继续生产和分析 ASD 受试者及其家庭的序列数据，ASC 受益于大量资源的利用，包括以外显子组聚合联盟 (ExAC) 为中心的资源。在布罗德研究所 (BI) 和 ASC 样本的全外显子组测序 (WES) 的支持下，在 NHGRI 中心向 BI 拨款的支持下，我们还计划新的研究途径，例如整合整体。基因组序列（WGS）数据，并以从常见变异研究中产生的想法为基础了解常见和罕见变异对风险的相互作用，通过这项新研究，我们将加速我们的总体目标，即 ASD 基因的识别，从而促进我们的长期目标。为 ASD 治疗目标的出现奠定基础。赋予 ASD 和相关神经发育障碍重大风险的基因可以构成此外，还进行了了解发病机制的研究以及新疗法的基础。我们根据过去十年的结果制定的中心假设是，罕见和常见的变异会增加自闭症谱系障碍的风险，但仅限于某些罕见的变异。重大风险。将通过以下具体目标来实现目标： 1) 生成和/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；寻找“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是重要的，因为它代表了 ASD 风险的第一步。研究旨在了解自闭症谱系障碍的发病机制，并开发治疗自闭症谱系障碍和病因相关的神经发育障碍的核心症状的药理学策略。我们认为，这项研究具有创新性，因为它使用了突破性和新颖的统计方法来识别风险变异和治疗。这是一种新的、本质上不同的 ASD 基因发现方法，它与现状有很大不同，并提供了方法实现这些重要目标。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.

通过使用群体参考样本来完善从头蛋白质截断变异在神经发育障碍中的作用。

DOI：
发表时间：
2017-04
期刊：
影响因子：
30.8
作者：
Kosmicki, Jack A;Samocha, Kaitlin E;Howrigan, Daniel P;Sanders, Stephan J;Slowikowski, Kamil;Lek, Monkol;Karczewski, Konrad J;Cutler, David J;Devlin, Bernie;Roeder, Kathryn;Buxbaum, Joseph D;Neale, Benjamin M;MacArthur, Daniel G;Wall, Dennis
通讯作者：
Wall, Dennis

A genome-wide scan statistic framework for whole-genome sequence data analysis.

用于全基因组序列数据分析的全基因组扫描统计框架。