A GENETIC LINKAGE STUDY OF GTS

本研究的长期目标是定位和表征抽动秽语综合征（GTS）和相关疾病的重要基因。最近的研究已经使我们对GTS和相关疾病的理解有了一些进展：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）似乎存在对于这种病症的表现重要的主要效应基因，以及4）使用受影响的同胞进行基因组筛选，对表明至少有两个区域可能具有GTS的易感基因座。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益于患者在他们的家庭中的复发;最终，澄清这种情况的遗传学可能阐明其发病机制。由该小组成员完成的先前研究表明，GTS和相关疾病的传播模式与对GTS表现有重大影响的基因的存在是一致的。以前的连锁研究，在精神病学雇用大的多代家庭已不成功的定位基因的重要表达的神经精神疾病。因此，我们进行了受影响的同胞对遗传连锁研究GTS。使用相距10 cM的高度多态性标记完成了基因组范围的筛选，并鉴定了两个高度提示性的基因组区域。在当前的应用中，我们建议收集额外的200个受影响的sibpairs来跟踪这些初步结果。我们还将跟踪过去十年研究的30个多代大家庭样本的所有结果。此外，将从南非的混合人群和遗传分离株中采集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查，并将其与两项研究的结果进行比较，这两项研究分别检查了德系犹太人GTS患者和来自哥斯达黎加分离株的患者。将利用连锁不平衡研究更准确地定位和鉴定感兴趣的基因。这项工作的长期目标是分离和表征GTS表现中重要的遗传位点。将通过对所有相关家庭成员进行直接结构化精神病学访谈获得关于GTS和相关疾病发生的表型数据。将采用最先进的非参数方法完成连锁和关联分析。

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.