Genetic & Environmental Predictors of Tourette Syndrome & OCD in Denmark

描述（由申请人提供）：在此，我们试图了解遗传和环境因素如何共同影响发展两种高度共病的神经精神障碍（图雷特综合征（TS）和强迫症（OCD））的风险。这些疾病由于其深刻的个人和社会代价而具有重大的公共卫生重要性。关于其病因学知之甚少，治疗，检测和预防策略不是最佳的或由病理生理学知识指导的。在其他精神疾病中（例如，基因组学已开始提供关于遗传结构的基本知识，确定生物学后续行动的特定基因座，并定位疾病中改变的途径。我们打算通过显著增加全球范围内对这两种疾病进行基因组分析的样本量来实现TS和OCD的这些相同进展，这是阐明这些相关疾病的基础生物学的第一步。 本项目将调查四个相互重叠的领域。首先，我们将发现与TS和OCD相关的常见和罕见变异的基因组位点。我们建议通过利用来自丹麦的存档血斑，以快速和具有成本效益的方式，将已发表的TS和OCD全基因组关联研究（GWAS）的样本量增加四倍。其次，我们将发现与TS和OCD相关的可复制结构变体（CNVs）。疾病相关的CNV是有吸引力的致病突变，因为通过改变基因剂量或结构，它们提供了作用方向和分子机制。第三，我们将确定TS，OCD及其主要合并症的共同遗传风险因素。在这里，我们测试是否临床合并症等同于遗传合并症。最后，我们将通过环境相互作用来识别易患TS和OCD的个体。我们获得了大量的纵向医学登记数据，每个人都将在这项研究中进行基因分型。这为通过环境相互作用识别基因创造了一个非凡的机会。总之，该项目可以增加对遗传和环境因素如何共同影响TS和OCD风险的高影响力理解，并导致新的机制假设。

DESCRIPTION (provided by applicant): Here we seek to understand how genetic and environmental factors jointly influence the risk of developing two highly co-morbid neuropsychiatric disorders, Tourette's Syndrome (TS) and Obsessive- Compulsive Disorder (OCD). These disorders are of major public health importance owing to their profound personal and societal costs. Little is known for certain about their etiology, and treatment, detection and prevention strategies are not optimal or directed by knowledge of pathophysiology. In other psychiatric disorders (e.g., schizophrenia, bipolar disorder and autism), genomics has begun to deliver fundamental knowledge about genetic architecture, identify specific loci for biological follow-up and localize pathways altered in disease. We intend to realize these same advances for TS and OCD by markedly increasing the worldwide sample size for genomic analysis of both disorders, in a first step toward elucidating the fundamental biology of these related conditions. Four overlapping areas will be investigated in this project. First, we will discover genomic loci harboring common and rare variation associated with TS and OCD. We propose to quadruple the sample size of published TS and OCD genome-wide association studies (GWAS), in a rapid and cost-effective manner by utilizing archived blood spots from Denmark. Second, we will discover replicable structural variants (CNVs) associated with TS and OCD. Disease-associated CNVs are attractive causative mutations since, by altering gene dosage or structure, they provide a direction of effect and molecular mechanism. Third, we will identify shared genetic risk factors for TS, OCD and its major comorbidities. Here we test whether clinical comorbidity equates to genetic comorbidity. Finally, we will identify gene by environment interactions predisposing individuals to TS and OCD. We have access to a wealth of longitudinal medical registry data for every individual that will be genotyped in this study. This creates an extraordinary opportunity to identify gene by environment interactions. In sum, this project could add a high-impact understanding of how genetic and environmental factors jointly influence risk of TS and OCD, and lead to new mechanistic hypotheses.