OCD: Novel Comparative Genomic Approaches to Identify Disease and Treatment Mechanisms

项目摘要 在这项研究中，我们试图了解遗传和环境因素如何共同影响这两个因素。 强迫症（OCD）的风险和治疗干预的结果。OCD 和相关疾病具有重大的公共卫生重要性，因为它们对个人和社会的影响是深刻的。 成本关于其病因学知之甚少，治疗，检测和预防策略也不确定。 最佳或由病理生理学知识指导。在其他精神疾病中（例如，精神分裂症， 双相情感障碍和自闭症），基因组学已经开始提供有关遗传的基本知识， 结构，确定生物学随访的特定位点，并定位疾病中改变的途径。我们打算 通过显著增加全世界基因组分析的样本量， 这是阐明这种疾病的基础生物学的第一步。 本项目将调查三个相互重叠的领域。首先，我们将收集世界上最大的丰富 强迫症病例的表型样本（N = 10，000）。为了以有效率和具成本效益的方式进行这项工作，我们会 利用挪威正在进行的全国性强迫症治疗研究和活跃的强迫症诊所网络 在瑞典表型将包括详细的临床表征（例如，合并症，症状 尺寸，治疗反应）和链接到瑞典和挪威的登记册，促进基因， 环境相互作用研究。其次，我们将对PsychChip GWAS阵列上的所有10，000个样本进行基因分型， （已获得> 30，000个匹配对照的基因型）。这将使我们能够发现基因组位点 包含与强迫症相关的常见和罕见变异。我们还将结合一个新的比较 基因组方法来解释这些基因组数据，利用高脸动物模型， 结构效度：犬强迫症。第三，我们将计算个人风险状况评分（GRS）， 测量强迫症的遗传易感性，并测试遗传易感性与一系列临床症状之间的相互作用。 (e.g.,对治疗的反应），流行病学（例如，父亲年龄，产科并发症，早年生活逆境， 社会经济地位）和遗传流行病学（例如，家族史）来自瑞典和 挪威注册我们希望这项研究能够提高我们对因果机制的理解 在强迫症，以期改善临床结果和减少慢性和社会成本。

PROJECT SUMMARY In this study we seek to understand how genetic and environmental factors jointly influence both the risk of developing Obsessive-Compulsive Disorder (OCD) and the outcome of treatment interventions. OCD and related 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 OCD by markedly increasing the worldwide sample size for genomic analysis, in a first step toward elucidating the fundamental biology of this condition. Three overlapping areas will be investigated in this project. First, we will collect the world's largest richly phenotyped sample of OCD cases (N = 10,000). To do this in an efficient and cost-effective manner, we will take advantage of an ongoing nationwide OCD treatment study in Norway and a network of active OCD clinics in Sweden. The phenotypes will include a detailed clinical characterization (e.g., comorbidities, symptom dimensions, treatment response) and links to the Swedish and Norwegian registers, facilitating gene by environment interaction studies. Second, we will genotype all 10,000 samples on the PsychChip GWAS array (genotypes for >30,000 matched controls are already available). This will allow us to discover genomic loci harboring common and rare variation associated with OCD. We will also incorporate a novel comparative genomic approach to interpret these genomic data, capitalizing on an animal model with high face and construct validity: canine compulsive disorder. Third, we will calculate individual risk profile scores (GRS) as a measure of genetic liability to OCD and test for interactions between genetic liability and a range of clinical (e.g., response to treatment), epidemiological (e.g., paternal age, obstetric complications, early life adversity, socioeconomic status) and genetic epidemiological (e.g., family history) variables from the Swedish and Norwegian registers. We expect this study to improve our understanding of the causal mechanisms implicated in OCD, with a view towards improving clinical outcomes and reducing chronicity and societal costs.