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

OCD：识别疾病和治疗机制的新比较基因组方法

• 批准号: 10161830
• 负责人: James Joseph Crowley
• 金额: $ 59.52万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161830
• 关键词: Animal Model; Area; Biological; Biology; Bipolar Disorder; Canis familiaris; Chronic; Clinic; Clinical; Clinical Data; Complex; Copy Number Polymorphism; Custom; DNA; Data; Detection; Dimensions; Disease; Drug Targeting; Environment; Environmental Risk Factor; Epidemiology; Etiology; Face; Family; Functional disorder; Genes; Genetic; Genetic Diseases; Genetic Risk; Genetic study; Genomic approach; Genomics; Genotype; Goals; Heritability; Human; Individual; Intervention; Knowledge; Learning; Link; Longterm Follow-up; Measures; Mental disorders; Meta-Analysis; Morbidity - disease rate; Norway; Obsessive-Compulsive Disorder; Outcome; Paternal Age; Pathway interactions; Phenotype; Prevention strategy; Public Health; Publishing; Recording of previous events; Resources; Risk; Sample Size; Sampling; Scandinavian; Schizophrenia; Societies; Socioeconomic Status; Source; Specialist; Sweden; Symptoms; Testing; Treatment outcome; United States National Institutes of Health; Update; Variant; associated symptom; autism spectrum disorder; base; case control; comparative genomics; cost; cost effective; design; disability; disorder control; disorder risk; early life adversity; early onset; epidemiologic data; exome; follow-up; gene environment interaction; genetic architecture; genetic risk factor; genome wide association study; genomic data; genomic locus; improved; neuropsychiatry; novel; obstetrical complication; predict clinical outcome; response; risk variant; sample collection; societal costs; tic-related; trait; treatment response

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.

项目摘要 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 发生强迫症（OCD）的风险和治疗干预措施的结果。强迫症 由于其深远的个人和社会，相关疾病具有重要的公共健康重要性 费用。关于其病因，治疗，检测和预防策略的知名度鲜为人知 最佳或由病理生理知识指导。在其他精神疾病中（例如，精神分裂症， 躁郁症和自闭症），基因组学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 通过明显增加全球样本量以进行基因组分析，实现强迫症的相同进步， 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，我们将收集世界上最大的丰富 OCD病例的表型样品（n = 10,000）。为了以一种有效且具有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强迫症治疗研究以及活跃的强迫症诊所网络 在瑞典。表型将包括详细的临床表征（例如合并症，症状 维度，治疗反应）以及与瑞典和挪威注册表的联系，促进基因 环境相互作用研究。第二，我们将在Psychchip GWAS阵列上基因型所有10,000个样本 （已经可以使用> 30,000个匹配的控件的基因型）。这将使我们发现基因组基因局 具有与强迫症相关的常见和罕见变化。我们还将结合一种新颖的比较 解释这些基因组数据的基因组方法，利用高面和高面动物模型 构建有效性：犬类强迫症。第三，我们将计算单个风险概况分数（GRS） 量度对强迫症的遗传责任和测试遗传责任与一系列临床之间的相互作用 （例如，对治疗的反应），流行病学（例如父亲年龄，产科并发症，早期生命逆境， 社会经济地位）和遗传流行病学（例如，家族史）变量 挪威注册。我们希望这项研究能够提高我们对涉及因果机制的理解 在强迫症中，为了改善临床结果并降低慢性和社会成本。

项目成果

Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: a preliminary investigation.

用深部脑刺激治疗的严重和难治性强迫症的基因组学：初步调查。

• DOI: 10.1101/2023.04.15.23288623
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Chen,LongLong;Naesström,Matilda;Halvorsen,Matthew;Fytagoridis,Anders;Mataix-Cols,David;Rück,Christian;Crowley,JamesJ;Pascal,Diana
• 通讯作者: Pascal,Diana

Polygenic Heterogeneity Across Obsessive-Compulsive Disorder Subgroups Defined by a Comorbid Diagnosis.

• DOI: 10.3389/fgene.2021.711624
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Strom NI;Grove J;Meier SM;Bækvad-Hansen M;Becker Nissen J;Damm Als T;Halvorsen M;Nordentoft M;Mortensen PB;Hougaard DM;Werge T;Mors O;Børglum AD;Crowley JJ;Bybjerg-Grauholm J;Mattheisen M
• 通讯作者: Mattheisen M

One versus two biological parents with mental disorders: Relationship to educational attainment in the next generation.

• DOI: 10.1017/s0033291722003506
• 发表时间: 2023-11
• 期刊: Psychological medicine
• 影响因子: 6.9
• 作者: Sidorchuk A;Brander G;Pérez-Vigil A;Crowley JJ;Larsson H;Lichtenstein P;Mataix-Cols D;Nordsletten AE
• 通讯作者: Nordsletten AE

Predicting remission after internet-delivered psychotherapy in patients with depression using machine learning and multi-modal data.

• DOI: 10.1038/s41398-022-02133-3
• 发表时间: 2022-09-01
• 期刊: TRANSLATIONAL PSYCHIATRY
• 影响因子: 6.8
• 作者: Wallert, John;Boberg, Julia;Kaldo, Viktor;Mataix-Cols, David;Flygare, Oskar;Crowley, James J.;Halvorsen, Matthew;Ben Abdesslem, Fehmi;Boman, Magnus;Andersson, Evelyn;Isacsson, Nils Hentati;Ivanova, Ekaterina;Ruck, Christian
• 通讯作者: Ruck, Christian

A population-based family clustering study of tic-related obsessive-compulsive disorder.

• DOI: 10.1038/s41380-019-0532-z
• 发表时间: 2021-04
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Brander G;Kuja-Halkola R;Rosenqvist MA;Rück C;Serlachius E;Fernández de la Cruz L;Lichtenstein P;Crowley JJ;Larsson H;Mataix-Cols D
• 通讯作者: Mataix-Cols D