Identification and Functional Assessment of Autism Susceptibility Genes

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，其特征是沟通缺陷，异常的社会互动，僵化或重复的兴趣和行为。尽管有强有力的证据表明遗传因素对ASD的病因起着重要的作用，但分离特定的致病遗传缺陷一直很困难。该项目将使用现有的DMA和来自AGRE和NIMH知识库的临床数据来搜索ASD易感基因。目标1将侧重于使用基于后验连锁概率（PPL）的替代贝叶斯方法进行连锁分析的基因型数据分析。之所以选择这种方法作为主要的分析方法，是因为它已被证明在从异质性疾病的基因定位研究中提取准确信息方面比目前任何基于模型或无模型的替代方法都要有效得多，极大地有助于易感基因的定位。目标2将重点关注目标1中确定的区域的精细链接和链接不平衡映射。通过1-2 cM密度的微卫星定位，PPL连锁峰将首先变窄，然后进行非常高密度的SNP定位。SNP基因分型将使用基于等位基因特异性连接的廉价、强大、灵活和可扩展的基因分型系统进行。结合连锁不平衡（LD）的PPL扩展将用于连锁峰内候选基因的LD定位。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，以及体外神经元培养和小鼠敲入蛋白来分析发育相关的细胞类型。在完成这些实验后，很可能会发现多个基因的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基因，使它们可能成为风险等位基因的候选者，并提供遗传证据，证明这些基因可能是ASD的易感性位点。为这些相关的单倍型生成的小鼠模型将为未来的发育、行为和毒理学实验提供更合适的系统。这些成就将导致重要的转化研究，以便更好地诊断、治疗和预防自闭症。

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.