A Genetic Linkage Study of GTS

GTS的遗传连锁研究

• 批准号: 7921394
• 负责人: Jeremiah M Scharf
• 金额: $ 98.27万
• 依托单位: TOURETTE ASSOCIATION OF AMERICA, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921394
• 关键词: Affect; Award; Behavioral; Biological Models; Blood specimen; Candidate Disease Gene; Child; Chromosome Mapping; Chromosome Markers; Chromosomes; Clinic; Clinical Investigator; Collaborations; DNA; DNA Resequencing; Data; Data Analyses; Diagnosis; Diagnostic; Disease; Family; Family member; Funding; Future; Genes; Genetic; Genome; Genomics; Genotype; Gilles de la Tourette syndrome; Goals; Individual; Inherited; International; Interview; Investigation; Lead; Link; Maps; North America; Parents; Participant; Phenotype; Population; Population Study; Predisposition; Research Personnel; Risk; SNP genotyping; Sampling; Science; Structure; Susceptibility Gene; Syndrome; Variant; base; clinical material; follow-up; gene function; genetic linkage; genetic linkage analysis; genetic pedigree; genome wide association study; genome-wide linkage; instrument; member; proband; repository; research study; transmission process

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.

描述(由申请人提供)：这项竞争性延续提案的重点是抽动症(TD)易感基因的定位和特征以及相关条件。这些研究人员是一个长期的国际合作组织--抽动症国际遗传学联合会(TSAICG)的成员。该小组成员之前完成的研究表明，TD和相关疾病的传播方式与对TD的表现有重大影响的基因的存在是一致的。在本次获奖期间，我们对受影响的同胞和多代家庭样本进行了全基因组连锁分析。这一结果有力地指向了2p染色体上的Td位点[-log(P)=4.00]，并为其他几个Td定位提供了证据，-log(P)得分在2.0到3.5之间。我们建议进行三项使用高通量SNP基因分型的遗传图谱研究：项目1将通过精细图谱基因分型来跟进我们的连锁发现，特别是2p；项目2将通过对从隔离人群中确定的800个三联体进行全基因组关联研究来寻找额外的TD基因座；项目3将跟进项目1和2的结果，在具有强大检测关联能力的样本中(n=7200)进行非常密集的SNP基因分型。项目3的结果将导致对少数位置候选基因的遗传调查。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。在这项提议的头两年抽样的新受试者的表型数据将通过对受影响的儿童和父母的直接半结构化访谈获得。建议进行其他分析，以更准确地定义TD表型的遗传成分。