1/4 - The Autism Sequencing Consortium: Discovering autism risk genes and how they impact core features of the disorder

1/4 - 自闭症测序联盟：发现自闭症风险基因以及它们如何影响该疾病的核心特征

• 批准号: 10580072
• 负责人: Joseph D. Buxbaum
• 金额: $ 41.53万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580072
• 关键词: ANK2 gene; Acceleration; Adult; Affect; Brain Diseases; Clinical; Copy Number Polymorphism; Data; Development; Diagnosis; Disease; Family; First Pregnancy Trimester; Foundations; General Population; Genes; Genetic; Genetic Risk; Genetic Variation; Goals; Heterogeneity; Individual; Inherited; International; Knowledge; Learning; Link; Mental disorders; Methods; Mission; Mutation; Neurodevelopmental Disorder; Nucleotides; Outcome; Pathogenesis; Pathway interactions; Pattern; Play; Population; Prevention; Process; Public Health; RFX3; Recommendation; Research; Research Project Grants; Resources; Risk; Role; Sampling; Sequence Analysis; Signal Transduction; Site; Source; Statistical Methods; Symptoms; Trans-Omics for Precision Medicine; United States National Institutes of Health; Variant; analytical method; autism spectrum disorder; cell type; cohort; developmental disease; disorder risk; exome; functional genomics; gain of function; gene discovery; genetic architecture; genomic data; improved; innovation; insertion/deletion mutation; insight; loss of function; neuropsychiatric disorder; novel; novel therapeutics; population based; rare variant; repetitive behavior; risk variant; sex; social deficits; therapeutic target; transmission process; whole genome

Project Summary/Abstract The past decade has seen outstanding advances in the genetics of autism spectrum disorder (ASD). Most of this progress has occurred by the study of rare genetic variation, especially de novo variation, with the Autism Sequencing Consortium (ASC) playing a central role. The ASC represents a coordinated international effort to identify ASD risk genes. In our most recent, unpublished, analyses of 72,410 individuals from ASD families, we identified 185 genes associated with risk (FDR < 0.05). Some of these genes have been linked to a broad array of developmental disorders, while others have not. Based on these results, we posit that some risk genes alter the core features of ASD, while creating fewer perturbations to other features of development: discovery of such genes will provide deeper insights into pathways disrupted in ASD. We will build on this progress by analysis of sequence data from three resources: ASD subjects and families; subjects with other developmental and neuropsychiatric disorders; and subjects from population samples. We plan new research focusing on interpretation of rare variation, including single nucleotide variation (SNV), indels, and copy number variation (CNV). Our key targets are inherited variants, including X-linked inherited variants, which to date have shown very little signal, and missense variants, for which signal has been confined to highly conserved substitutions. We anticipate doubling the number of ASD genes discovered, ~ 400, by increasing the number of families analyzed and by refined methods to interpret inherited and missense variation. And, in parallel, we expect to resolve critical aspects of ASD genetic architecture and to unveil key aspects of what makes ASD and its core features – social deficits and restrictive and repetitive behaviors – different from other neurodevelopmental disorders. To discover ASD risk genes with a distinct effect on ASD, we have the following specific aims: 1) To amalgamate existing and emerging whole exome and whole genome sequence data; 2) To develop new analytical methods and analyze the accumulated sequence data; and, 3) To contrast ASD and other neurodevelopmental disorder risk genes, examining developmental profiles, cell types implicated, and whether variants in the same gene differ in how they affect risk for ASD and other neurodevelopmental and psychiatric disorders. With 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. 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 research proposed is innovative, in our opinion, because it uses groundbreaking and novel statistical methods for identifying risk variants for ASD.

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。大多数 这种进步是通过研究自闭症的罕见遗传变异，尤其是从头变异而发生的 测序联盟（ASC）发挥着核心作用。 ASC代表着协调的国际努力 识别ASD风险基因。在我们最近对来自ASD家庭的72,410个人的最新，未发表的分析中，我们 确定了与风险相关的185个基因（FDR <0.05）。这些基因中的一些已与广泛的 一系列发育障碍，而其他人则没有。基于这些结果，我们海报说某些风险基因 改变ASD的核心特征，同时对开发的其他特征产生更少的扰动：发现 此类基因将提供对ASD中断的途径的更深入的见解。我们将以这一进展为基础 分析来自三个资源的序列数据：ASD主题和家庭；具有其他发展的主题 和神经精神疾病；和人口样本的受试者。我们计划关注的新研究 罕见变化的解释，包括单核苷酸变化（SNV），Indels和拷贝数变化 （CNV）。我们的主要目标是继承的变体，包括X连锁的继承变体，迄今已显示的变体 信号和错义变体很少，该信号被限制在高度组成的替换中。 我们预计通过增加家庭数量，发现的ASD基因数量约为400 分析并通过精制方法来解释遗传和错义变化。而且，同时，我们期望 解决ASD遗传结构的关键方面，并揭示使ASD及其核心的关键方面 特征 - 社会缺陷以及限制性和重复行为 - 与其他神经发育不同 疾病。为了发现对ASD有明显影响的ASD风险基因，我们具有以下特定目的：1） 将整个外显子和整个基因组序列数据混合在一起； 2）开发新的 分析方法并分析累积序列数据； 3）对比ASD和其他 神经发育障碍风险基因，检查发育概况，实施细胞类型以及是否是否 同一基因中的变体在影响ASD和其他神经发育和精神病的风险方面不同 疾病。通过这项新研究，我们将加速我们的整体目标，这就是ASD的识别 基因，从而支持我们建立基础的长期目标 出现。我们的理由是，基因的识别会议会议对ASD和相关 神经发育障碍可以构成研究发病机理的基础，以及基础 用于新型疗法。我们的中心假设是基于过去十年的结果制定的 - 罕见 常见变化对ASD的风险有所贡献，但只有某些稀有变体会议很大 风险。在我们看来，提出的研究是创新的，因为它使用了开创性和新颖的统计 识别ASD风险变体的方法。