Identification and Functional Assessment of Autism Susceptibility Genes

描述（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、社交互动异常以及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自闭症谱系障碍的病因有重要影响，但分离出特定的致病遗传缺陷仍然很困难。该项目将使用 AGRE 和 NIMH 存储库中的现有 DMA 和临床数据来寻找 ASD 易感基因。目标 1 将重点关注使用基于连锁后验概率 (PPL) 的替代贝叶斯连锁分析方法来分析基因型数据。该方法被选为主要分析方法，因为它已被证明在从异质性疾病的基因图谱研究中提取准确信息方面比任何当前基于模型或无模型的替代方法要有效得多，极大地帮助了易感基因的定位。目标 2 将重点关注目标 1 中确定的区域的精细连锁和连锁不平衡作图。PPL 连锁峰最初将通过 1-2 cM 密度微卫星作图缩小，然后进行极高密度 SNP 作图。 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。包含连锁不平衡 (LD) 的 PPL 扩展将用于连锁峰内候选基因的 LD 作图。目标 3 将使用淋巴母细胞和死后样本以及体外神经元培养物和小鼠基因敲入来研究相关单倍型是否在功能上改变候选基因，以分析发育相关的细胞类型。这些实验完成后，很可能会鉴定出多个基因的 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相关基因，使它们可能成为风险等位基因的候选者，并提供这些基因可能充当 ASD 易感位点的遗传证据。将为其中一些相关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适合的系统。这些成就将带来重要的转化研究，以便为自闭症谱系障碍开发更好的诊断、治疗和预防方法。

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.