2/4 The Autism Sequencing Consortium: Discovering autism risk genes and how they impact core features of the disorder

2/4 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: 10579317
• 负责人: Mark Joseph Daly
• 金额: $ 38.37万
• 依托单位: BROAD INSTITUTE, INC.
• 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/10579317
• 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 In our most recent, unpublished, analyses of 72,410 individuals from ASD families, we identified 185 genes associated with risk (FDR 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 neuro- psychiatric 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 as- pects 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.

项目概要/摘要 过去十年，自闭症谱系障碍 (ASD) 的遗传学取得了显着进展。 这一进展是通过对自闭症患者罕见遗传变异（尤其是新生变异）的研究而取得的 测序联盟 (ASC) 发挥着核心作用 ASC 代表了国际社会的协调努力。 在我们最近对来自 ASD 家族的 72,410 名个体进行的未发表的分析中，我们确定了 ASD 风险基因。 确定了 185 个与风险相关的基因 (FDR < 0.05)。 发育障碍，而其他人则没有。根据这些结果，我们假设一些风险基因发生了改变。 ASD 的核心特征，同时对发展的其他特征造成更少的干扰：发现这样的 基因将为自闭症谱系障碍中被破坏的途径提供更深入的见解，我们将通过分析来巩固这一进展。 来自三个来源的序列数据：自闭症谱系障碍受试者和家庭；患有其他发育和神经疾病的受试者； 我们计划开展新的研究，重点是解释。 罕见变异，包括单核苷酸变异 (SNV)、插入缺失和拷贝数变异 (CNV)。 目标是遗传变异，包括 X 连锁遗传变异，迄今为止显示的信号非常少， 和错义变体，我们预计其信号仅限于高度保守的替换。 通过增加分析的家族数量和通过 同时，我们期望解决关键问题。 自闭症谱系障碍遗传结构的各个方面，并揭示自闭症谱系障碍的关键方面及其核心特征——社交 缺陷以及限制性和重复性行为——与其他神经发育障碍不同。 ASD 风险基因对 ASD 有明显影响，我们有以下具体目标： 1）合并现有的 以及新兴的全外显子组和全基因组序列数据；2) 开发新的分析方法和 分析积累的序列数据；3) 对比 ASD 和其他神经发育障碍风险 基因，检查发育概况、相关细胞类型以及同一基因的变异 这项新研究揭示了它们如何影响自闭症谱系障碍以及其他神经发育和精神疾病的风险。 我们将加速我们的总体目标，即自闭症谱系障碍基因的鉴定，促进我们的长期 我们的长期目标是为自闭症谱系障碍的治疗目标奠定基础。 鉴定出对自闭症谱系障碍和相关神经发育障碍具有重大风险的基因 了解发病机制的研究基础，以及新疗法的基础。 – 根据过去十年的结果制定 – 罕见和常见的变异会额外贡献 ASD 的风险，但只有某些罕见的变异会带来重大风险。在我们看来，这项研究是创新的。 意见，因为它使用开创性和新颖的统计方法来识别自闭症谱系障碍的风险变异。