Population Genetic Mapping of Tourette Syndrome

描述（由申请人提供）：这是一份旨在确定抽动秽语综合征（TS）遗传基础的竞争性续批申请。该项目是基于全基因组群体遗传图谱的方法，即使用密集的，高度多态性的短串联重复序列（STR）标记，以确定与TS连锁不平衡（LD）的区域。LD定位研究的重点是独立确定TS患者（及其父母）从哥斯达黎加（CVCR）的中央谷隔离人群。PI和合作者一直在改进分析此类LD数据的方法。 在上一次颁奖期间，我们从CVCR中采样了先证者及其父母，并启动了全基因组LD筛查。基因型数据的初步分析表明TS易感基因的几种可能的定位。特别是，强烈的LD与TS表型上观察到染色体17q25，在该区域中，连锁TS先前已建议由其他组。在延续这项资助时，将完成CVCR样本的样本收集、基因分型和全基因组LD图谱绘制。 全基因组筛选中突出显示的区域将在来自相同群体的额外TS样本中进行随访。后续研究中的阳性结果将用作选择基因组区域进行精细定位研究的指导。将使用STR和单核苷酸多态性（SNP）对CVCR样本和合作者样本进行这些精细的基因分型研究，以确定TS易感基因的位置。在这些区域中最有希望的区域，我们将使用现有的SNP以及我们将在研究样本中识别的SNP来筛选候选基因。通过完成该奖项，我们的目标是确定一个或多个与TS易感性相关的序列变异。

DESCRIPTION (provided by applicant): This is an application for competitive renewal of a grant aimed at identifying the genetic basis of Tourette syndrome (TS). The project is based on a genomewide population genetic mapping approach, that is, using densely spaced, highly polymorphic short tandem repeat (STR) markers to identify regions of linkage disequilibrium (LD) with TS. The LD mapping study is focused on independently ascertained TS patients (and their parents) from the isolated population of the Central Valley of Costa Rica (CVCR). The PI and collaborators have been refining approaches for analyzing such LD data. During the previous award, we sampled probands and their parents from the CVCR and initiated a genomewide LD-screen. Preliminary analyses of genotype data suggest several possible localizations for TS susceptibility genes. In particular, strong LD with the TS phenotype was observed on chromosome 17q25, a region in which linkage to TS had previously been suggested by other groups. In the renewal of this grant, sample collection, genotyping and genome-wide LD mapping will be completed for the CVCR samples. Regions highlighted from the whole genome screen will be followed up in additional TS samples from the same population. Positive findings in the follow-up studies will be used as a guide to select genome regions for fine-mapping studies. These fine scale genotyping studies of the CVCR samples and samples from collaborators, using STRs and single nucleotide polymorphisms (SNPs), will be carried out to pinpoint the location of TS susceptibility genes. In the most promising of these regions we will screen candidate genes using existing SNPs as well as using SNPs that we will identify in the study samples. By the completion of the award, we aim to identify one or more sequence variants associated with TS susceptibility.