A GENETIC LINKAGE STUDY OF GTS

这项研究的长期目标是定位和表征Gilles de la Tourette综合征(GTS)及其相关疾病的重要基因。最近的研究在我们对GTS和相关疾病的理解上取得了一些进展：1)GTS的表型表达范围更大；2)GTS和相关疾病比以前认为的要常见得多；3)似乎有一些对这种疾病的表现具有重要作用的基因；4)使用受影响的同胞对进行基因组筛查表明，至少有两个区域可能包含GTS的易感基因。GTS和相关疾病的流行及其对患者的衰弱影响使这些疾病成为一个重大的公共卫生问题。了解GTS的遗传学和相关行为将直接有益于担心其家庭复发的患者；最终，澄清这种疾病的遗传学可能会阐明其发病机制。该小组成员之前完成的研究表明，GTS和相关疾病的传播方式与对GTS的表现有重大影响的基因的存在是一致的。以前在精神病学中利用多代大家庭进行的连锁研究在定位神经精神障碍表达的重要基因方面并不成功。因此，我们开展了GTS的受影响同胞对遗传连锁研究。利用相隔10 cM的高度多态标记完成了全基因组的筛选，并鉴定出两个高度提示的基因组区域。在目前的应用中，我们建议再收集200个受影响的同胞对，以跟踪这些初步结果。我们还将跟进过去十年来研究的30个多代大家庭的样本中的所有结果。此外，DNA样本将从GTS患者及其父母那里收集，这些患者来自南非的一个混合种群和一个基因分离株。一个单独的基因组筛查将与南非样本一起完成，并与两项研究的结果进行比较，这两项研究检查了德系克肯纳齐GTS患者和哥斯达黎加分离株的患者。连锁不平衡研究将被用来更准确地定位和识别感兴趣的基因。这项工作的长期目标是分离和鉴定在GTS表现中重要的遗传位点。表型数据将通过对所有相关家庭成员的直接结构化精神病学访谈获得，涉及GTS的发生和相关条件。链接和关联分析将使用最先进的非参数方法完成。

The long term objective of this research is the localization and characterization of genes important for Gilles de la Tourette syndrome (GTS) and related conditions. Recent research has led to several advances in our understanding of GTS and related conditions: 1) there is a greater range of phenotypic expression for GTS; 2) GTS and related disorders are much more common than had previously been thought; 3) there appear to be genes of major effect important for the manifestation of this condition and 4) a genome screen using affected sib-pairs suggests that there are at least two regions that may harbor susceptibility loci for GTS. The prevalence of GTS and associated illnesses and their debilitating effects on those afflicted makes these conditions a major public health problem. Understanding the genetics of GTS and associated behaviors will be of direct benefit to patients concerned about recurrence in their families; ultimately, clarifying the genetics of this condition may elucidate its pathogenesis. Previous studies completed by members of this group suggest that the mode of transmission of GTS and related disorders is consistent with the existence of genes that have a significant impact on the manifestation of GTS. Previous linkage studies in psychiatry employing large multigenerational families have been unsuccessful in locating genes important for the expression of neuropsychiatric disorders. Thus, we undertook an affected sib-pair genetic linkage study of GTS. A genome wide screen was completed using highly polymorphic markers 10cM apart and two highly suggestive genomic regions were identified. In the current application, we are proposing to collect an additional 200 affected sibpairs to follow-up these initial results. We will also follow-up all results in a sample of 30 large multigenerational families that have been studied for the past decade. Furthermore, DNA samples will be collected from GTS patients and their parents from both an admixed population and a genetic isolate in South Africa. A separate genome screen will be completed with the South African sample and compared to results from two studies examining Ashkenazi GTS patients and patients from an isolate in Costa Rica. Linkage disequilibrium studies will be utilized to more accurately localize and identify genes of interest. The long term goal of this work is to isolate and characterize genetic loci important in the manifestation of GTS. Phenotypic data will be obtained by direct structured psychiatric interview of all pertinent family members with respect to the occurrence of GTS and related conditions. Linkage and association analyses will be completed with state-of-the-art non-parametric methods.