A Genetic Linkage Study of GTS

描述（由申请人提供）：该竞争性延续提案的重点是抽动秽语障碍（TD）和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，Tourette综合征协会国际遗传学联盟（TSAICG）。该小组成员完成的先前研究表明，TD和相关疾病的传播模式与对TD表现有重大影响的基因的存在是一致的。在目前的奖项，我们进行了全基因组连锁分析，我们的样本受影响的同胞对和多代家庭。结果强烈地指向染色体2 p [-log（p）= 4.00]上的TD位点，并且还提供了几个附加TD定位的证据，-log（p）分数范围为2.0至3.5。我们提出了三个利用高通量SNP基因分型的遗传作图研究：项目1将用精细作图基因分型来跟踪我们的连锁发现，特别关注2 p;项目2将通过对800个从孤立群体中确定的trios进行全基因组关联研究来寻找额外的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，并具有检测关联的能力。项目3的结果将导致对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。将通过对受影响儿童和父母双方进行直接半结构化访谈，获得本提案前两年新样本的表型数据。提出了额外的分析，以更准确地定义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.