权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Integrating common and rare genetic variation in autism spectrum disorder

整合自闭症谱系障碍中常见和罕见的遗传变异

基本信息

批准号：
10548147
负责人：
Daniel Weiner
金额：
$ 4.03万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548147
关键词：
Adult Affect Biological Biological Process Biology Cell Nucleus Code Communication Data Set Disease Doctor of Philosophy Environment Family Fellowship Foundations Functional disorder Funding Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Variation Genome Genomic Segment Goals Heritability Impairment Mediating Mediation Mentorship Methods Modeling Neurons Pathway interactions Pharmacological Treatment Physicians Population Research Training Resources Risk Risk Factors Scientist Symptoms Test Result Testing Therapeutic Tissues Training Uncertainty United States National Institutes of Health Untranslated RNA Variant Work autism spectrum disorder brain tissue career causal variant cell type cohort exome sequencing genetic risk factor genome wide association study genome-wide improved neural neuropsychiatry novel programs rare variant repetitive behavior social communication statistics therapeutic development transcriptomics transmission process

项目摘要

Project Summary Autism spectrum disorder (ASD) is common and often disabling. Currently, there are no pharmacologic treatments for its core symptoms: impairment in social communication and restricted/repetitive behavior. The high heritability of ASD suggests that understanding its genetic risk factors will help define ASD pathophysiology and facilitate therapeutic development. The largest genetic risk factor for ASD on a population level is common polygenic variation, the additive influence of thousands of small effect SNPs estimated with GWAS. However, interpretation of polygenic risk is challenging: most disease-associated SNPs are non- coding, the identity of their target gene(s) is uncertain, and their influence on gene expression is often unknown. Thus, the genes and biological pathways affected by common polygenic risk for ASD remain poorly defined. In contrast, recent studies of rare coding variation have associated >70 genes with ASD (“ASD Genes”), which collectively highlight ASD-relevant biological processes. To define the biology of polygenic risk for ASD, it is critically important to understand the degree to which polygenic risk converges with the genes and pathways identified through rare variant studies. We propose to apply three novel statistical and functional approaches to (a) interpret common polygenic risk for ASD and (b) assess the convergence of common polygenic risk for ASD and ASD Genes. In Aim 1, we introduce the Stratified-polygenic Transmission Disequilibrium Test (S-pTDT), which is powered to examine polygenic risk arising from small regions of the genome. We will use S-pTDT to quantify the concentration of polygenic risk for ASD in and around ASD Genes. In Aim 2, we introduce an approach to understand how polygenic risk influences gene expression, leveraging a large single-nucleus transcriptomic dataset of adult human brain tissue. We will use this approach to test the hypothesis that polygenic risk for ASD decreases expression of ASD Genes, and to nominate candidate causal genes in genomic regions with heightened polygenic relevance in ASD. In Aim 3, we introduce the Abstract Mediation Model (AMM), which quantifies the proportion of common-variant heritability mediated by gene sets while accounting for uncertainty in the gene targets of non-coding SNPs. We will apply AMM to estimate the extent to which polygenic risk for ASD is mediated by ASD Genes and other ASD-relevant gene sets. These Aims will improve our understanding of the genetic underpinnings of ASD, strengthen biological and therapeutic hypotheses, and generate methods applicable to other neuropsychiatric conditions. Finally, this research training will occur in the stimulating environment of the Harvard/MIT MD/PhD Program and Broad Institute of MIT and Harvard. Under the guidance of his sponsors, the fellowship PI will complete five training goals that will create the foundation for a career as an NIH-funded physician-scientist.

项目总结