A GENETIC LINKAGE STUDY OF GTS

本研究的长期目标是定位和表征对吉勒德拉图雷特综合征（GTS）及相关疾病重要的基因。最近的研究使我们对GTS及其相关疾病的理解取得了一些进展：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)似乎有一些基因对这种疾病的表现起着重要的作用；4)使用受影响的兄弟姐妹对进行的基因组筛选表明，至少有两个区域可能存在GTS的易感位点。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主要的公共卫生问题。了解GTS的遗传学和相关行为将直接有利于关注其家族复发的患者；最终，阐明这种情况的遗传学可能阐明其发病机制。本课题组成员之前完成的研究表明，GTS及相关疾病的传播方式与存在对GTS表现有重大影响的基因是一致的。先前的精神病学连锁研究采用大的多代家庭已经成功定位基因重要的神经精神疾病的表达。因此，我们进行了GTS的影响兄弟对遗传连锁研究。利用相距10cM的高度多态性标记完成基因组宽筛选，鉴定出两个高度暗示的基因组区域。在目前的申请中，我们建议再收集200对受影响的兄弟姐妹来跟进这些初步结果。我们还将对过去十年研究的30个多代大家庭样本的所有结果进行跟踪调查。此外，将从南非的一个混合人群和一个遗传分离物中收集GTS患者及其父母的DNA样本。将对南非样本进行单独的基因组筛选，并将其与两项研究的结果进行比较，该研究对德系犹太人GTS患者和哥斯达黎加分离的患者进行了检查。连锁不平衡研究将用于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表征在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关于GTS发生和相关疾病的直接结构化精神病学访谈获得。联动和关联分析将完成与最先进的非参数方法。

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.