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 In our most recent, unpublished, analyses of 72,410 individuals from ASD families, we identified 185 genes associated with risk (FDR 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.

项目总结/文摘