A Comprehensive Approach to Identification of Autism Susceptibility Genes

鉴定自闭症易感基因的综合方法

基本信息

批准号：
7597202
负责人：
DANIEL H GESCHWIND
金额：
$ 289.55万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7597202
关键词：
Address Affect African American Alleles Autistic Disorder Biocompatible Materials Bioinformatics Candidate Disease Gene Cell Line Childhood Chromosome abnormality Chromosomes, Human, Pair 17 Classification Code Collection Communication Communities Complex Copy Number Polymorphism Cytogenetics DNA Resequencing Data Data Coordinating Center Databases Detection Diagnosis Disease Etiology European Family Family member Fluorescent in Situ Hybridization Foundations Fragile X Syndrome Functional RNA Functional disorder Funding Gene Combinations Genes Genetic Genetic Heterogeneity Genetic Variation Genome Genome Scan Genotype Haplotypes Head circumference Heterogeneity Incidence Internet Investigation Language Language Delays Literature Maps Methods Microsatellite Repeats Microscopic Minority Molecular Mutation National Institute of Mental Health Online Systems Parents Pathway Analysis Pathway interactions Phenotype Population Predisposition Proteins Publishing Research Research Personnel Resolution Resources SNP genotyping Sample Size Sampling Siblings Signal Transduction Site Staging Stratification Susceptibility Gene Syndrome Testing Update Variant Work autism spectrum disorder base cohort comparative genomic hybridization cost effective data exchange delay sex endophenotype follow-up gene interaction genetic analysis genetic resource genetic risk factor genetic variant genome wide association study genome-wide neuropsychiatry positional cloning proband programs sex social communication

项目摘要

DESCRIPTION (provided by applicant): Autism is a devastating neuropsychiatric condition with unknown pathophysiology. Autism spectrum disorders (ASD) have an estimated incidence of 1/200 and thus are more common than many other childhood disorders. Although ASD have a multifactorial etiology, it has a large genetic component. It is also becoming clear that comprehensive efforts involving large sample sizes and methods to reduce heterogeneity are necessary to achieve maximal power to identify disease critical regions narrow enough to permit positional cloning of autism susceptibility genes. The investigators in this application aim to continue their collaborative effort that has produced and enhanced a highly successful open data and biomaterials resource for the research community, the Autism Genetic Resource Exchange (AGRE). This collaborative network application involving six research sites and the AGRE DCC, will systematically and comprehensively investigate the genetics of ASD to identify rare mutations, chromosomal abnormalities, and common variation contributing to ASD susceptibility. Specifically, they will enrich existing resources by adding 400 simplex families, including 200 families of African American descent, in addition to phenotype enrichment. The large overall sample size permits stratification of families based on analysis of heritable quantitative and qualitative endophenotypes. It further allows independent confirmation of loci as demonstrated for chromosome 17 and provides adequate sample for whole genome association studies to find loci with adequate power. The investigators will perform follow up linkage studies to confirm several new loci identified based on autism-related endophenotypes or co- variants, such as language delay, sex, and head circumference. In parallel, comparative genomic hybridization (CGH) using 500k SNP arrays will be performed, yielding the highest resolution molecular karyotypes and providing a resource on genome wide copy number variation (CNV) in ASD. CNV identified will be followed in family members and controls using QPCR and FISH. The use of SNP genotyping for CNV detection in ASD probands further provides for significant economies, since additional genotyping need only be conducted in the parents for efficient whole genome association studies. Regions or genes identified by linkage will be followed up by efficient, staged dense SNP genotyping. CNV assessment and WGA will also yield candidates that will be integrated with the linkage results for focused confirmatory studies, including re-sequencing to identify and confirm potentially causal genetic variants. Genetic risk factors identified in the mostly white European sample will be tested for association in the African American sample to determine whether these cohorts share the same genetic risk factors. All phenotypic and genotype data will be made accessible via the Internet on a rolling basis, including minority families, further enhancing the value of this resource to the community.

描述（由申请人提供）：自闭症是一种具有未知病理生理学的毁灭性神经精神病疾病。自闭症谱系障碍（ASD）的估计发病率为1/200，因此比许多其他儿童疾病更为普遍。尽管ASD具有多因素病因，但它具有较大的遗传成分。同样，还需要清楚的是，涉及大量样本量和减少异质性的方法的全面努力对于达到最大能力以识别疾病关键区域的最大能力是必要的，以允许自闭症易感基因的位置克隆。本申请中的研究人员旨在继续他们的协作努力，并为研究社区（自闭症遗传资源交换（CLES））生产并增强了非常成功的开放数据和生物材料资源。这种涉及六个研究站点和协议DCC的协作网络应用将系统，全面地研究ASD的遗传学，以鉴定罕见的突变，染色体异常和常见变异，并导致ASD易感性。具体而言，除了表型富集外，他们还将增加400个单纯族家庭（包括200个非裔美国人血统的家庭）来丰富现有资源。大量的总体样本量允许基于对可遗传定量和定性内表型的分析进行分层。它进一步允许独立确认基因座，如染色体17所证明的，并为整个基因组关联研究提供了足够的样品，以找到具有足够功率的基因座。研究人员将进行后续联系研究，以确认基于自闭症相关的内型型或co的几个新基因座，例如语言延迟，性别和头围。同时，将执行使用500K SNP阵列的比较基因组杂交（CGH），从而产生最高分辨率的分子核型，并在ASD中提供有关基因组宽拷贝数（CNV）的资源。使用QPCR和FISH的家庭成员和对照中，将遵循确定的CNV。在ASD概率中，使用SNP基因分型在CNV检测中进一步提供了重要的经济体，因为仅需要在父母中进行额外的基因分型来进行有效的整个基因组关联研究。通过链接确定的区域或基因将以有效的，密集的SNP基因分型为之后。 CNV评估和WGA还将产生候选者，这些候选者将与重点验证性研究的联系结果整合在一起，包括重新续订以识别和证实潜在的因果遗传变异。在非裔美国人样本中，将测试大多数欧洲白人样本中确定的遗传危险因素，以确定这些同龄人是否具有相同的遗传危险因素。所有表型和基因型数据都将在包括少数族裔家庭在内的互联网上通过互联网获取，从而进一步增强了该资源对社区的价值。