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: 10095318
• 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/10095318
• 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 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.

项目摘要 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。强迫症是主要的公共卫生问题 由于其巨大的个人和社会代价，它具有重要意义。对其病因还知之甚少，而且 治疗、检测和预防策略不是最佳的，也不是以病理生理学知识为指导的。在……里面 其他精神障碍(如自闭症、智力障碍、精神分裂症、多动症) 大量受试者的测序(WES)已经开始提供关于遗传学的基本知识 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 通过以下方式显著增加全球强迫症受试者数量，实现同样的强迫症进展 WES数据，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，我们将从5100个数据中生成WES数据 强迫症受试者和3000名血统匹配的对照组，均来自瑞典和挪威。对个体进行排序 来自这些国家的信息提供了了解共病情况的实质性优势。我们会打电话给 测序数据中罕见的遗传变异。其次，我们将把这些新数据与现有的WE结合起来 约1,400例强迫症病例和约8,000名对照的数据。这将增加识别强迫症风险基因的能力，我们 将使用现有的分析方法和新的分析方法相结合。第三，我们将进一步细化 了解强迫症的遗传结构，重点了解强迫症风险与其他疾病风险的关系 神经发育障碍，包括抽动障碍、自闭症、多动症、精神分裂症和躁郁症。 结合来自多个大型研究的WES数据将增强识别共享基因座的能力，并开始 识别更具特异性的强迫症基因座。总体而言，我们相信这项研究将提高我们对 强迫症的遗传危险因素，以期改善临床结果，减少慢性病和 社会成本。