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

表型谱基础上的遗传机制的全基因组解剖