Identification and Functional Assessment of Autism Susceptibility Genes

自闭症易感基因的鉴定和功能评估

• 批准号: 7686691
• 负责人: VERONICA J. VIELAND
• 金额: $ 26.27万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686691
• 关键词: Accounting; Affect; Alleles; Autistic Disorder; Behavior; Behavioral; Brain; Candidate Disease Gene; Chromosome Mapping; Clinical Data; Collection; Communication; Complex; Data; Data Linkages; Data Sources; Development; Diagnosis; Disease; Family; Future; Gene Expression; Genes; Genetic; Genome; Genotype; Haplotypes; In Situ Hybridization; In Vitro; Individual; Lead; Ligation; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Maps; Measures; Methods; Microsatellite Repeats; Minor; Modeling; Mus; Mutation; National Institute of Mental Health; Neurodevelopmental Disorder; Neurons; Pattern; Population; Predisposition; Probability; Procedures; Regulation; Risk; SNP genotyping; Sampling; Signal Transduction; Single Nucleotide Polymorphism Map; Social Interaction; Susceptibility Gene; System; Techniques; Toxicology; Transcript; Translational Research; Validation; autism spectrum disorder; base; cell type; density; falls; flexibility; genetic linkage analysis; in vitro Assay; interest; lymphoblastoid cell line; mouse model; novel; repository; research study

DESCRIPTION (provided by applicant): The autism spectrum disorders (ASD) are a group of serious neurodevelopmental disorders characterized by deficits in communication, abnormal social interactions, and rigid or repetitive interests and behaviors. Although there is strong evidence of an important genetic contribution to the cause of ASD, the isolation of specific causative genetic defects has been difficult. This project will use existing DMA and clinical data from the AGRE and NIMH repositories to search for ASD susceptibility genes. Aim 1 will focus on the analysis of genotype data using an alternative, Bayesian approach to linkage analysis, based on the posterior probability of linkage (PPL). This method was selected as the main analysis approach as it has been demonstrated to be far more effective in extracting accurate information from gene-mapping studies of heterogeneous disorders than any of the current model-based or model-free alternatives, greatly aiding the localization of susceptibility genes. Aim 2 will focus on fine linkage and linkage disequilibrium mapping of regions identified in Aim 1. PPL linkage peaks will initially be narrowed through 1-2 cM density microsatellite mapping, followed by very high density SNP mapping. SNP genotyping will be conducted using an inexpensive, robust, flexible and scalable genotyping system based on allele-specific ligation. An extension of the PPL that incorporates Linkage Disequilibrium (LD) will be used for LD mapping of candidate genes within the linkage peaks. Aim 3 will investigate whether associated haplotypes functionally alter the candidate genes using lymphoblastoid and post-mortem samples as well as in vitro neuronal cultures and mouse knock-ins to analyze developmentally relevant cell types. Upon completion of these experiments, it is likely that ASD-associated alleles for multiple genes will be identified. Through our extensive functional analysis, we will be able to demonstrate that some of the associated haplotypes functionally alter the associated genes, making them likely candidates for risk alleles and providing genetic evidence that these genes likely act as ASD susceptibility loci. The mouse models that will be generated for some of these associated haplotypes will provide a more amenable system for future developmental, behavioral and toxicology experiments. These accomplishments will lead to important translational research so that better diagnoses, treatments and preventions can be developed for ASD.

描述（由申请人提供）：自闭症谱系障碍（ASD）是一组严重的神经发育障碍，其特征是以交流，异常的社会互动以及僵化或重复的利益和行为和行为的缺陷为特征。尽管有强有力的证据表明对ASD的原因有重要的遗传贡献，但很难分离特定的病因遗传缺陷。该项目将使用现有的DMA和NIMH存储库中的临床数据来搜索ASD易感基因。 AIM 1将根据链接后验概率（PPL）的替代性贝叶斯方法来重点关注基因型数据的分析。该方法被选为主要分析方法，因为与当前基于模型或无模型的替代方案相比，它在从异质性疾病的基因映射研究中提取准确的信息方面具有更有效的效果，极大地有助于易感基因的定位。 AIM 2将集中于AIM 1中确定的区域的细胞连接和连锁不平衡映射。PPL链接峰最初将通过1-2 cm密度的微卫星映射范围缩小，然后进行非常高密度的SNP映射。 SNP基因分型将使用基于等位基因特异性连接的廉价，健壮，柔性和可扩展的基因分型系统进行。结合连锁不平衡（LD）的PPL的扩展将用于在连锁峰内的候选基因的LD映射。 AIM 3将研究相关的单倍型是否在功能上使用淋巴母细胞和验尸样品以及体外神经元培养物和小鼠敲知以分析发育中相关的细胞类型。完成这些实验后，可能会发现与多个基因相关的等位基因。通过我们广泛的功能分析，我们将能够证明某些相关的单倍型在功能上改变了相关的基因，使它们可能候选风险等位基因，并提供遗传证据，表明这些基因可能是ASD易感性基因座。这些相关的单倍型将生成的小鼠模型将为将来的发育，行为和毒理学实验提供更正常的系统。这些成就将导致重要的转化研究，因此可以为ASD开发更好的诊断，治疗方法和预防措施。