Whole genome dissection of genetic mechanisms that underlie the phenotypic spectrum of autism

自闭症表型谱基础遗传机制的全基因组剖析

• 批准号: 10891821
• 负责人: Jonathan Sebat
• 金额: $ 73.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2024-09-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10891821
• 关键词: Address; Autism Diagnosis; Brain region; Cell physiology; Cognition; Cognitive; Data Set; Development; Dissection; Family; Female; Frequencies; Gene Cluster; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genome; Heritability; Individual; Inherited; Knowledge; Link; Modality; Molecular; Motor; Nature; Pathway interactions; Phenotype; Risk; SNP genotyping; Sample Size; Sex Chromosomes; Social Behavior; Susceptibility Gene; Symptoms; Tandem Repeat Sequences; Time; Variant; autism spectrum disorder; cell type; cognitive function; de novo mutation; exome; genome analysis; genome wide association study; genomic data; insight; novel; phenotypic data; polygenic risk score; protective effect; rare variant; repetitive behavior; risk variant; sex; trait; whole genome

Whole genome dissection of genetic mechanisms that underlie the phenotypic spectrum of autism It is recognized that the genetic etiology of Autism Spectrum Disorder (ASD) is multifactorial, with contributions from multiple factors including de novo mutations, rare inherited variants, polygenic risk scores (PRS) and sex. Genetic studies have identified >100 ASD susceptibility genes. However, studies have each been carried out one modality at a time (GWAS, exome or genome). Consequently, there are major gaps in our understanding of the genetic mechanisms underlying ASD. For instance, the heritability of ASD explained has not been systematically characterized for all forms of rare and common variant risk, including structural variant (SVs) and tandem repeats (TRs). Non-additive effects of rare and common variants have not been systematically explored. Furthermore, it is not understood how rare and common variants, in genes and neurodevelopmental pathways, influence ASD symptom domains and ultimately converge to a diagnosis of ASD. Recent studies from our labs (PMID: 35654974, 33442040) have shown that multiple factors act in combination in the individual to determine risk for ASD, and each genetic factor has distinct phenotypic correlates. These results highlight knowledge that can be gained from an integrated analysis of genomic and phenotypic datasets in ASD families. With a vast increase in sample size, we have sufficient power to address these questions in the following aims (1) Complete assembly of genomic and phenotypic data on 62,328 ASD families (N = 204,428 subjects) and perform a whole genome analysis of the heritability explained by common and rare SNVs, SVs, and TRs; (2) Investigate novel genetic mechanisms that could explain missing heritability, including gene x gene and gene x sex, interactions; and (3) Dissect the genetic effects of molecular and cellular pathways on cognitive traits. An integrated analysis of variant types across a range of frequencies could set a new bar for the heritability of ASD explained, could yield clues to the nature of the unexplained, and could provide mechanistic basis insights into the effects of genes on cognition

基于表型谱的基因组的全基因组解剖 自闭症 人们认识到自闭症谱系障碍（ASD）的遗传病因是多因素的， 从多个因素的贡献，包括从头突变，罕见的遗传变体， 多基因风险评分（PR）和性别。遗传研究已经确定了> 100个ASD易感性 基因。但是，每一次研究都进行了一种模式（GWAS，Exome或 基因组）。因此，我们对遗传机制的理解存在主要差距 基础ASD。例如，ASD解释的遗传力并非系统地。 以所有形式的稀有和常见变体风险（包括结构变体（SV））进行特征 和串联重复（TRS）。稀有和常见变体的非加性影响尚未 系统地探索。此外，尚不理解在 基因和神经发育途径，影响ASD症状结构域，最终 收敛于ASD的诊断。我们实验室的最新研究（PMID：35654974，33442040） 已经表明，多个因素在个人组合起作用以确定ASD的风险， 并且每个遗传因子都有不同的表型相关。这些结果突出了知识 可以从ASD中基因组和表型数据集的综合分析中获得 家庭。随着样本量的巨大增加，我们有足够的能力来解决这些问题 以下目的中的问题（1）完全组装基因组和表型数据 62,328个ASD家族（n = 204,428名受试者），对整个基因组分析 遗传力用常见和稀有的SNV，SVS和TRS解释； （2）研究新遗传 可以解释缺失遗传力的机制，包括基因X基因和基因X性别， 互动； （3）剖析分子和细胞途径对认知的遗传作用 特质。对一系列频率的变体类型的集成分析可能会设置一个新的栏 为了解释ASD的遗传力，可以为无法解释的本质提供线索，并 可以提供有关基因对认知影响的机械基础见解