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: 7127605
• 负责人: JAMES H. MILLONIG
• 金额: $ 44.06万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7127605
• 关键词: autism; cell line; family genetics; gene expression; gene mutation; genetic models; genetic screening; genetic susceptibility; genetically modified animals; human data; human tissue; in situ hybridization; laboratory mouse; linkage disequilibriums; linkage mapping; lymphoblast; mental health epidemiology; model design /development; northern blottings; postmortem; quantitative trait loci; single nucleotide polymorphism; statistics /biometry; tissue /cell culture

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 DNA and clinical data from the ACRE 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，其特征是沟通障碍、异常的社会互动以及僵化或重复的兴趣和行为。虽然有强有力的证据表明遗传因素对ASD的病因有重要贡献，但分离特定的致病遗传缺陷一直很困难。该项目将使用来自ACRE和NIMH储存库的现有DNA和临床数据来搜索ASD易感基因。目标1将集中在基因型数据的分析，使用另一种方法，贝叶斯方法的连锁分析，后验概率连锁（PPL）的基础上。这种方法被选为主要的分析方法，因为它已被证明是更有效地提取准确的信息，从基因图谱研究的异质性疾病比任何目前的基于模型或无模型的替代品，极大地帮助定位的易感基因。目标2将侧重于目标1中确定的区域的精细连锁和连锁不平衡作图。PPL连锁峰最初将通过1- 2cM密度的微卫星定位，然后通过非常高密度的SNP定位来缩小。SNP基因分型将使用基于等位基因特异性连接的廉价、稳健、灵活和可扩展的基因分型系统进行。PPL的扩展，包括连锁不平衡（LD）将用于LD定位候选基因内的连锁峰。目的3将研究相关的单倍型是否在功能上改变候选基因，使用淋巴母细胞样和死后样本，以及在体外神经元培养和小鼠敲入分析发育相关的细胞类型。在完成这些实验后，很可能将鉴定出多个基因的ASD相关等位基因。通过我们广泛的功能分析，我们将能够证明一些相关的单倍型在功能上改变了相关的基因，使它们成为风险等位基因的可能候选者，并提供遗传证据表明这些基因可能作为ASD易感基因。这些相关单倍型中的一些将产生的小鼠模型将为未来的发育、行为和毒理学实验提供更适合的系统。这些成就将导致重要的转化研究，以便为ASD开发更好的诊断，治疗和预防。