2/2 Rare Genetic Variation and Risk for Obsessive Compulsive Disorder

2/2 罕见的基因变异和强迫症的风险

• 批准号: 10318565
• 负责人: James Joseph Crowley
• 金额: $ 7.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10318565
• 关键词: Adolescent; Affect; Area; Attention deficit hyperactivity disorder; Awareness; Biological; Biology; Bipolar Disorder; Child; Chronic; Clinical; Clinical Research; Code; Collection; Complex; Copy Number Polymorphism; Country; DNA; DNA Resequencing; Data; Data Set; Detection; Development; Disease; Environmental Risk Factor; Etiology; Functional disorder; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genotype; Gilles de la Tourette syndrome; Goals; Human; Individual; Inherited; Intellectual functioning disability; Knowledge; Learning; Life; Mental disorders; Methods; Molecular; Molecular Target; Neurodevelopmental Disorder; Norway; Nucleotides; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Outcome; Parents; Pathway interactions; Play; Population; Prevention strategy; Price; Proteins; Psychiatric Diagnosis; Psychiatrist; Public Health; Publishing; Research; Risk; Role; Sampling; Schizophrenia; Site; Specificity; Sweden; System; Tic disorder; Variant; analytical method; autism spectrum disorder; base; case control; cell type; comorbidity; disorder risk; exome; exome sequencing; follow-up; gene discovery; genetic architecture; genetic risk factor; genome-wide; improved; insertion/deletion mutation; method development; neuropsychiatry; new therapeutic target; non-genetic; novel; phenotypic data; power analysis; psychiatric comorbidity; psychiatric genomics; risk variant; skills; societal costs; tic-related

Project Summary In this study we seek to understand how rare genetic variation in all protein coding genes (the exome) influences the risk of developing obsessive-compulsive disorder (OCD). OCD is of major public health importance owing to its profound personal and societal costs. Little is known for certain about its etiology, and treatment, detection and prevention strategies are not optimal or directed by knowledge of pathophysiology. In other psychiatric disorders (e.g., autism, intellectual disability, schizophrenia, ADHD), whole exome sequencing (WES) in large numbers of subjects 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 number of OCD subjects with WES data, in a first step toward elucidating the fundamental biology of this condition. Three overlapping areas will be investigated in this project. First, we will produce WES data from 5,100 OCD subjects and 3,000 ancestry-matched controls, all from Sweden and Norway. Sequencing individuals from these countries provides the substantial advantage of knowing about co-morbid conditions. We will call rare genetic variation from the sequencing data. Second, we will combine these new data with existing WES data for ~1,400 OCD cases and ~8,000 controls. This will increase power to identify OCD risk genes, which we will do using a combination of existing and novel analytical methods. Third, we will further refine our understanding of the genetic architecture of OCD, focusing on the relationship of OCD risk to risk for other neurodevelopmental disorders, including tic disorders, autism, ADHD, schizophrenia and bipolar disorder. Combining WES data from multiple large studies will enhance power to identify shared loci and begin to identify loci with greater specificity for OCD. Overall, we believe this study will improve our understanding of genetic risk factors for OCD, with a view towards improving clinical outcomes and reducing chronicity and societal costs.

项目概要 在这项研究中，我们试图了解所有蛋白质编码基因（外显子组）中罕见的遗传变异 影响患强迫症（OCD）的风险。强迫症是重大公共卫生问题 由于其巨大的个人和社会成本而具有重要意义。关于其病因知之甚少，并且 治疗、检测和预防策略不是最佳的，也不是由病理生理学知识指导的。在 其他精神疾病（例如自闭症、智力障碍、精神分裂症、多动症）、全外显子组 大量受试者的测序（WES）已开始提供有关遗传的基础知识 结构，确定生物学后续的特定位点并定位疾病改变的途径。我们打算 通过显着增加全球强迫症受试者的数量，在强迫症方面取得了同样的进展 WES 数据是阐明这种情况的基本生物学原理的第一步。 该项目将调查三个重叠区域。首先，我们将从 5,100 个数据中生成 WES 数据 强迫症受试者和 3,000 名血统匹配的对照者，全部来自瑞典和挪威。对个体进行测序 来自这些国家的人提供了了解共病状况的巨大优势。我们会打电话 测序数据中罕见的遗传变异。其次，我们会将这些新数据与现有的WES结合起来 约 1,400 例强迫症病例和约 8,000 例对照的数据。这将增强我们识别强迫症风险基因的能力 将使用现有和新颖的分析方法的组合来完成。三是我们将进一步完善 了解强迫症的遗传结构，重点关注强迫症风险与其他风险之间的关系 神经发育障碍，包括抽动障碍、自闭症、多动症、精神分裂症和双相情感障碍。 结合多项大型研究的 WES 数据将增强识别共享基因座的能力，并开始 识别对 OCD 具有更高特异性的基因座。总的来说，我们相信这项研究将加深我们对 强迫症的遗传风险因素，以改善临床结果并减少慢性病和 社会成本。