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

基本信息

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
项目类别：
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

项目摘要

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的罕见遗传变异如何影响发生强迫症（OCD）的风险。强迫症是主要的公共卫生重要的是由于其深远的个人和社会成本。关于其病因的众所周知，很少有人知道治疗，检测和预防策略不是病理生理知识的最佳或指导。在其他精神疾病（例如自闭症，智力残疾，精神分裂症，多动症）大量受试者的测序（WES）已经开始提供有关遗传的基本知识建筑，确定生物随访的特定基因座，并定位疾病改变的途径。我们打算通过明显地增加了全球的强迫症受试者，以实现强迫症的同样进步 WES数据，迈向阐明这种情况的基本生物学的第一步。该项目将研究三个重叠的区域。首先，我们将产生5,100的WES数据强迫症受试者和3,000个祖先匹配的对照，全部来自瑞典和挪威。测序个体来自这些国家提供了了解合并症条件的实质性优势。我们会打电话测序数据的罕见遗传变异。其次，我们将将这些新数据与现有WES结合在一起约1,400例OCD病例和约8,000个对照的数据。这将增加识别强迫症风险基因的能力，我们将使用现有和新颖的分析方法的组合来完成。第三，我们将进一步完善我们的了解强迫症的遗传结构，重点关注强迫症风险与其他风险的关系神经发育障碍，包括抽动疾病，自闭症，ADHD，精神分裂症和躁郁症。将来自多个大型研究的WES数据结合在一起将增强识别共享基因座的能力并开始确定针对强迫症的特异性更特异性的基因座。总体而言，我们认为这项研究将提高我们对强迫症的遗传危险因素，以改善临床结果并降低慢性和社会成本。