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

项目总结 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 患强迫症(OCD)的风险和治疗干预的结果。强迫症 以及相关的疾病，由于其深刻的个人和社会影响，具有重大的公共卫生重要性 成本。人们对其病因知之甚少，治疗、检测和预防策略也不清楚 最佳的或由病理生理学知识指导的。在其他精神障碍中(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关于基因的基本知识 架构，为生物追踪确定特定的位置，并定位在疾病中改变的路径。我们打算 通过显著增加全球基因组分析的样本量，实现强迫症的同样进步， 这是阐明这种疾病的基本生物学的第一步。 本项目将对三个重叠区域进行调查。首先，我们将收集世界上最大的富豪 强迫症病例表型样本(N=10,000)。为了以有效率和符合成本效益的方式做到这一点，我们将 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特征(例如，合并症、症状 维度、治疗反应)和与瑞典和挪威登记的链接，通过以下方式促进基因 环境相互作用研究。其次，我们将对心理芯片GWAS阵列上的所有10,000个样本进行基因分型 (已经有30,000名配对对照的基因型别可用)。这将使我们能够发现基因组基因座 有与强迫症相关的常见和罕见的变异。我们还将纳入一种新颖的比较 基因组学方法来解释这些基因组数据，利用一个高面孔的动物模型和 结构效度：犬强迫症。第三，我们将计算个人风险概况得分(GRS)作为 强迫症遗传易感性的测量和遗传易感性与一系列临床疾病之间的交互作用的测试 (如对治疗的反应)、流行病学(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)变量 挪威的登记处。我们期望这项研究能提高我们对其中涉及的因果机制的理解。 在强迫症方面，以期改善临床结果，降低慢性病和社会成本。

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.