1/2 Rare Genetic Variation and Risk for Obsessive Compulsive Disorder

1/2 罕见的基因变异和强迫症的风险

• 批准号: 10318678
• 负责人: DOROTHY E GRICE
• 金额: $ 69.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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/10318678
• 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， 影响患强迫症的风险。强迫症是一种重要的公共卫生问题 这是由于其深刻的个人和社会成本。关于其病因学知之甚少， 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、智力残疾、精神分裂症、ADHD），整个外显子组 大量受试者的基因测序（WES）已经开始提供有关遗传学的基础知识， 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 通过显著增加世界范围内强迫症受试者的数量， WES数据，在阐明这种情况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，我们将从5100个 强迫症受试者和3,000名血统匹配的对照组，均来自瑞典和挪威。个体测序 来自这些国家的信息提供了了解共病状况的实质性优势。我们称 罕见的基因变异其次，我们将联合收割机将这些新数据与现有的WES相结合 约1，400名强迫症患者和约8，000名对照者的数据。这将增加识别强迫症风险基因的能力， 将使用现有的和新的分析方法相结合。第三，我们将进一步完善 了解强迫症的遗传结构，重点是强迫症风险与其他风险的关系， 神经发育障碍，包括抽动障碍、自闭症、ADHD、精神分裂症和双相情感障碍。 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 找出对强迫症更有特异性的基因座总的来说，我们相信这项研究将提高我们对 强迫症的遗传风险因素，以期改善临床结果和减少慢性病， 社会成本。