A Genetic Linkage Study of GTS

描述（由申请人提供）：本竞争性延续申请的重点是图雷特病（TD）及相关疾病易感基因的定位和表征。研究人员是长期国际合作的成员，图雷特综合症协会国际遗传学联盟（TSAICG）。本课题组成员之前完成的研究表明，TD及相关疾病的传播方式与存在对TD表现有重大影响的基因是一致的。在本次颁奖期间，我们对受影响的兄弟姐妹和多代家庭样本进行了全基因组连锁分析。结果有力地指向了染色体2p上的一个TD位点[-log(p) = 4.00]，并且还为其他几个TD定位提供了证据，-log(p)得分在2.0到3.5之间。我们建议使用高通量SNP基因分型进行三个遗传作图研究：项目1将使用精细作图基因分型跟踪我们的连锁发现，特别关注2p；项目2将通过对从孤立人群中确定的800个三联体进行全基因组关联研究，寻找更多的TD位点；项目3将跟进项目1和2的结果，在样本（n=7200）中对一组非常密集的snp进行基因分型，具有很强的检测相关性的能力。项目3的结果将导致少量位置候选基因的遗传研究。将对通过上述研究确定的最有希望的候选基因进行功能研究。在本提案的前两年，新受试者的表型数据将通过对受影响儿童和父母双方的直接半结构化访谈获得。提出了更多的分析来更准确地定义TD表型的遗传成分。

DESCRIPTION (provided by applicant): The focus of this competing continuation proposal is the localization and characterization of susceptibility genes for Tourette's Disorder (TD) and related conditions. The investigators are members of a longstanding international collaboration, the Tourette Syndrome Association International Consortium on Genetics (TSAICG). Previous studies completed by members of this group suggest that the mode of transmission of TD and related disorders is consistent with the existence of genes that have a significant impact on the manifestation of TD. During the current award we conducted a genomewide linkage analysis of our samples of affected sibpair and multigenerational families. The results pointed strongly to a TD locus on Chromosome 2p [-log(p) = 4.00] and also provided evidence for several additional TD localizations, with -log(p) scores ranging from 2.0 to 3.5. We are proposing three genetic mapping studies using high-throughput SNP genotyping: Project 1 will follow up our linkage findings with fine-mapping genotyping, focusing particularly on 2p; Project 2 will search for additional TD loci through a whole genome association study on 800 trios ascertained from isolated populations; Project 3 will follow up the results of Projects 1 and 2, with a very dense set of SNPs to be genotyped in a sample (n=7200) with substantial power to detect association. The results of Project 3 will lead to genetic investigation of a small number of positional candidate genes. Functional studies of the most promising candidate genes identified through the above studies will be undertaken. Phenotypic data for new subjects sampled during the first two years of this proposal will be obtained by direct semi-structured interview of affected children and both parents. Additional analyses are proposed to define more accurately the inherited components of the TD phenotype.