3/4 The Autism Sequencing Consortium: Discovering autism risk genes and how they impact core features of the disorder

3/4 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: 10420099
• 负责人: KATHRYN M ROEDER
• 金额: $ 40.48万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 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/10420099
• 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 In our most recent, unpublished, analyses of 72,410 individuals from ASD families, we identified 185 genes associated with risk (FDR 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.

项目总结/摘要 在过去的十年里，自闭症谱系障碍（ASD）的遗传学取得了显著的进展。大部分 这一进展是通过研究自闭症患者罕见的遗传变异，特别是新生变异而取得的。 测序联盟（ASC）发挥着核心作用。ASC代表了一种协调的国际努力， 确定ASD风险基因。在我们最近未发表的对72，410名ASD家庭成员的分析中，我们 发现185个与风险相关的基因（FDR < 0.05）。其中一些基因与一系列广泛的 而其他人则没有。基于这些结果，我们认为，一些风险基因改变， ASD的核心特征，同时对其他发育特征产生较少的干扰：发现这种 基因将提供更深入的了解在ASD中断的途径。我们将在此基础上，通过分析 来自三个资源的序列数据：ASD受试者和家庭;其他发育和神经系统疾病的受试者， 精神疾病;和来自人群样本的受试者。我们计划进行新的研究， 包括单核苷酸变异（SNV）、插入缺失和拷贝数变异（CNV）。我们的关键 靶是遗传变异，包括X连锁遗传变异，迄今为止显示出非常小的信号， 和错义变体，其信号已被限制于高度保守的取代。我们预计 通过增加分析的家族数量， 精细的方法来解释遗传和错义变异。同时，我们希望解决关键问题- ASD遗传结构的观点，并揭示ASD及其核心特征的关键方面-社会 缺陷和限制性和重复性行为-不同于其他神经发育障碍。发现 ASD风险基因对ASD有明显的影响，我们有以下具体目标：1）合并现有的 和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， 分析累积的序列数据;和，3）对比ASD和其他神经发育障碍风险 基因，检查发育概况，涉及的细胞类型，以及同一基因中的变体是否在 它们如何影响ASD和其他神经发育和精神疾病的风险。通过这项新的研究 我们将加速我们的总体目标，即确定ASD基因，从而促进我们长期的研究， 长期目标是建立ASD治疗靶点的基础。我们的理由是， 对ASD和相关神经发育障碍具有显著风险的基因的鉴定可以形成 了解发病机制的研究基础，以及新疗法的基础。我们的核心假设 - 根据过去十年的结果制定的-是罕见和常见的变异有助于增加 ASD的风险，但只有某些罕见的变异赋予重大风险。这项研究是创新的，在我们的 观点，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。