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

4/4 - 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: 10433743
• 负责人: Stephan Sanders
• 金额: $ 39.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433743
• 关键词: ANK2 gene; Adult; Affect; Brain Diseases; Centers for Disease Control and Prevention (U.S.); 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; base; 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; restrictive repetitive behavior; risk variant; sex; social deficits; therapeutic target; 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 In our most recent, unpublished, analyses of 72,410 individuals from ASD families, we identified 185 genes associated with risk (FDR 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一个宽的数组相关 发展疾病，而其他疾病则没有。基于这些结果，我们海报认为某些风险基因改变了 ASD的核心特征，同时对开发的其他特征造成更少的扰动：发现此类 基因将为ASD中断的途径提供更深入的见解。我们将通过分析 来自三个资源的序列数据：ASD主题和家庭；具有其他发育和神经的受试者 精神疾病；和人口样本的受试者。我们计划专注于解释的新研究 罕见变化，包括单核苷酸变异（SNV），indels和拷贝数变化（CNV）。我们的钥匙 目标是继承的变体，包括X连锁的继承变体，迄今为止显示的信号很少， 和错义变体，为此信号局限于高度保守的替代。 通过增加分析的家庭数量和通过 精致的方法来解释继承和错义变化。而且，同时，我们期望解决关键的AS- ASD遗传建筑的景点，并揭示使ASD及其核心特征的关键方面 - 社会特征 缺陷以及限制性和重复行为与其他神经发育障碍不同。发现 ASD风险基因对ASD有明显影响，我们具有以下特定目的：1）合并现有的 以及出现的整个外显子组和整个基因组序列数据； 2）开发新的分析方法和 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，检查发育曲线，实现的细胞类型以及在同一基因中的变体是否不同 它们如何影响ASD和其他神经发育和精神疾病的风险。通过这项新研究 我们将加速我们的整体目标，即ASD基因的识别，从而支持我们的长期 建立基础的术语目标是从中出现治疗目标的基础。我们的理由是 识别基因会议会议对ASD和相关神经发育障碍的重大风险可以形成 了解发病机理的研究基础，也是新疗法的基础。我们的中心假设 - 基于过去十年的结果制定的 - 罕见和常见的变化又有贡献 ASD的风险，但只有某些稀有变体会议会议很大的风险。提出的研究是创新的，在我们的 意见，因为它使用开创性和新颖的统计方法来识别ASD的风险变体。