Genomics of PTSD and Related Traits

PTSD 和相关特征的基因组学

• 批准号: 10292943
• 负责人: JOEL GELERNTER
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292943
• 关键词: 3-Dimensional; Alcohol consumption; Alcohol dependence; Alzheimer' s Disease; Asians; Biological; Biology; Chromosome Mapping; Chronic Post Traumatic Stress Disorder; Collaborations; Communities; Copy Number Polymorphism; Crohn' s disease; DSM-IV; Data; Diagnosis; Disease; Electronic Medical Records and Genomics Network; Etiology; Functional disorder; General Population; Genes; Genetic; Genomics; Hand; Immune; Impaired cognition; Latino; Link; Maps; Mendelian randomization; Methods; Multiple Sclerosis; Nicotine Dependence; Opiate Addiction; Outcome; Pathogenesis; Patients; Phenotype; Population; Population Genetics; Post-Concussion Syndrome; Post-Traumatic Stress Disorders; Research; Rheumatoid Arthritis; Risk; Risperidone; Sampling; Schizophrenia; Soldier; South Asian; Subgroup; Substance Use Disorder; Symptoms; System; Testing; Trauma; United States Department of Veterans Affairs; Veterans; Work; base; biobank; comorbidity; cooperative study; data sharing; experience; follow-up; gene environment interaction; genetic risk factor; genome wide association study; genome-wide; genome-wide analysis; genomic locus; improved; insight; military service; military veteran; polygenic risk score; programs; prospective; psychiatric genomics; rare variant; response; risk variant; schizophrenia risk; trait; whole genome

ABSTRACT Posttraumatic stress disorder (PTSD) is a major problem among military Veterans, yet its pathophysiology is poorly understood. The Veterans Affairs (VA) Million Veteran Program (MVP) is an ideal setting for study of this problem, and we are completing a Cooperative Studies Program project (CSP#575B), in the MVP context, to identify genetic risk factors relevant to PTSD and related traits. Our CSP-MVP Alpha Project for the Genomics of PTSD has been highly successful at mapping gene loci, so far for PTSD re-experiencing and other related phenotypes (such as “maximum habitual alcohol use”). Although PTSD GWAS data per se are under analysis, considerable work still needs to be done to fully develop and maximize the scientific value of the MVP for PTSD and related phenotypes, as the analyzable MVP sample continues to grow. Over the course of this project, we have assembled an expert team well- qualified to continue the work. To continue this work, we propose a set of extended analyses in a larger sample, and post-GWAS analyses. With more subjects there will be increased power to map relevant traits; we will continue GWAS of PTSD and related traits in the expanded sample. There is very high comorbidity of PTSD with substance use disorder traits; we propose to explore SUDs as well, including alcohol dependence, opioid dependence, nicotine dependence, and other SUDs. We will investigate single-gene and polygenic overlap between PTSD and related traits. We will study traits phenotypically associated with PTSD, such as cognitive decline, Alzheimer’s disease, persistent post-concussive symptoms, and immune-related disorders (such as Crohn’s disease, rheumatoid arthritis, and multiple sclerosis) in the MVP sample. We will use approaches that permit testing of causality among these correlated traits (e.g., Mendelian Randomization, MR). We will complete a phenomewide association study (PheWAS) of PTSD top GWAS-identified genes (e.g., CRHR1 and others), PTSD polygenic risk score (PRS) analysis within MVP, and MR to detect causal mechanisms related to PTSD pathogenesis. With the aim of maximizing the scientific value of these data and sharing them with the scientific community, we will also explore the possibility of replication of our findings in collaboration with other EHR-linked biobank consortia such as the Psych-EMERGE network; and the Psychiatric Genomics Consortium PTSD group (in which we participate presently). Finally, the MVP sample is suitable for advancing work in many populations that are generally understudied. We will investigate psychiatric trait-relevant population genetics of AAs, Latinos, East Asians, and South Asians, and other populations in the MVP system, and we will work to maximize information from, and identify results relevant to, all populations.

抽象的 创伤后应激障碍（PTSD）是退伍军人的主要问题，但是 它的病理生理学知之甚少。退伍军人事务（VA）百万退伍军人计划 （MVP）是研究此问题的理想场所，我们正在完成合作研究 计划项目（CSP＃575b），在MVP上下文中，以确定与 PTSD和相关特征。我们针对PTSD基因组学的CSP-MVP alpha项目已经 在映射基因位点方面非常成功，到目前为止，PTSD重新体验和其他相关性 表型（例如“最大习惯性饮酒”）。尽管PTSD GWAS数据本身是 在分析下，仍需要做大量工作才能充分发展和最大化 MVP对PTSD和相关表型的科学价值，作为可分析的MVP样本 继续增长。在这个项目的过程中，我们组建了一个专家团队 有资格继续工作。为了继续这项工作，我们提出了一系列扩展分析 更大的样本和GWAS后分析。 随着更多的主题，将增加绘制相关特征的力量。我们将继续 扩展样本中PTSD和相关性状的GWA。合并症很高 具有药物使用障碍特征的PTSD；我们建议也探索泡沫，包括酒精 依赖性，OIOID依赖性，尼古丁依赖性和其他SUD。 我们将研究PTSD和相关性状之间的单基因和多基因重叠。 我们将研究与PTSD表型相关的特征，例如认知下降，阿尔茨海默氏症 疾病，持续的脑震荡症状和免疫相关疾病（例如克罗恩 MVP样本中的疾病，类风湿关节炎和多发性硬化症）。我们将使用 可以在这些相关性状中测试因果关系的方法 随机化，MR）。我们将完成PTSD的现象全面协会研究（PHEWAS） 顶级GWAS识别基因（例如CRHR1等），PTSD多基因风险评分（PRS） MVP内的分析和MR检测与PTSD发病机理有关的因果机制。 为了最大化这些数据的科学价值并与它们共享 科学界，我们还将探讨复制我们发现的可能性 与其他与EHR相关的生物银行联盟（Psych-Exerge Network）合作； 以及精神病基因组学联盟PTSD小组（我们参与现在）。 最后，MVP样本适合在许多人群中推进工作 一般理解。我们将研究AAS的精神病特征人群遗传学， 拉丁美洲人，东亚人，南亚人以及MVP系统中的其他人群，我们将 工作以最大化信息，并确定与所有人群相关的结果。