Genetic & Environmental Predictors of Tourette Syndrome & OCD in Denmark

描述(由申请人提供)：在这里，我们试图了解遗传和环境因素如何共同影响两种高度共病的神经精神障碍的风险，即抽动症(TS)和强迫症(OCD)。这些疾病具有重大的公共卫生意义，因为它们造成了巨大的个人和社会代价。对其病因知之甚少，治疗、检测和预防策略也不是最佳的，也不是由病理生理学知识指导的。在其他精神疾病(如精神分裂症、双相情感障碍和自闭症)中，基因组学已经开始提供关于遗传结构的基本知识，确定用于生物随访的特定位点，并定位疾病中改变的路径。我们打算通过显著增加用于这两种疾病的基因组分析的全球样本大小来实现对TS和OCD的同样的进展，这是阐明这些相关疾病的基本生物学的第一步。 本项目将调查四个重叠区域。首先，我们将发现与TS和强迫症相关的基因组基因座具有常见和罕见的变异。我们建议将已发表的TS和强迫症全基因组关联研究(GWAS)的样本量扩大四倍，通过利用丹麦存档的血点，以快速和经济的方式。其次，我们将发现与TS和OCD相关的可复制结构变体(CNV)。疾病相关的CNV是很有吸引力的致病突变，因为它们通过改变基因剂量或结构，提供了作用方向和分子机制。第三，我们将确定TS、强迫症及其主要并存的共同遗传风险因素。在这里，我们测试临床共病是否等同于遗传共病。最后，我们将确定易患TS和OCD的基因与环境的交互作用。我们可以访问这项研究中将进行基因分型的每个人的大量纵向医疗登记数据。这为识别基因与环境的相互作用创造了一个非同寻常的机会。总而言之，这个项目可以增加对遗传和环境因素如何共同影响TS和OCD风险的高影响力的理解，并导致新的机制假说。

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.