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）是退伍军人的一个主要问题，但 退伍军人事务部 (VA) 百万退伍军人计划对其病理生理学知之甚少。 （MVP）是研究这个问题的理想环境，我们正在完成一项合作研究 计划项目 (CSP#575B)，在 MVP 背景下，识别与以下疾病相关的遗传风险因素： 我们的 PTSD 基因组学 CSP-MVP Alpha 项目已经完成。 到目前为止，在绘制基因位点图谱方面非常成功，用于 PTSD 重新体验和其他相关 表型（例如“最大习惯性饮酒”）虽然 PTSD GWAS 数据本身是 经分析，要充分发展和最大限度地发挥 MVP 对 PTSD 和相关表型的科学价值，作为可分析的 MVP 样本 在这个项目的过程中，我们已经组建了一支专家团队。 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。 随着主题的增加，绘制相关特征的能力也会增强，我们将继续这样做； 扩展样本中 PTSD 和相关特征的 GWAS 合并症非常高。 具有物质使用障碍特征的 PTSD；我们建议也探索 SUD，包括酒精 依赖、阿片类药物依赖、尼古丁依赖和其他 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 相关的表型特征，例如认知能力下降、阿尔茨海默病 疾病、持续性脑震荡后症状和免疫相关疾病（例如克罗恩病） 疾病、类风湿性关节炎和多发性硬化症）我们将在 MVP 样本中使用。 允许测试这些相关特征之间的因果关系的方法（例如孟德尔 随机化，MR）。我们将完成 PTSD 的全表型关联研究 (PheWAS)。 GWAS 识别的顶级基因（例如 CRHR1 等）、PTSD 多基因风险评分 (PRS) MVP 和 MR 内的分析可检测与 PTSD 发病机制相关的因果机制。 旨在最大限度地发挥这些数据的科学价值并与公众共享 科学界，我们还将探索复制我们的发现的可能性 与其他与 EHR 相关的生物样本库联盟（例如 Psych-EMERGE 网络）合作； 以及精神病基因组学联盟 PTSD 小组（我们目前参与其中）。 最后，MVP 样本适合在许多人群中推进工作，这些人群 我们将研究 AA 的精神特质相关群体遗传学， 拉丁美洲人、东亚人、南亚人以及 MVP 体系中的其他人群，我们将 努力最大限度地获取所有人群的信息并确定与所有人群相关的结果。