Genomics of PTSD and Related Traits

摘要 创伤后应激障碍(PTSD)是退伍军人中的一个主要问题，但 人们对其病理生理学知之甚少。退伍军人事务部(VA)百万退伍军人计划 (MVP)是研究这一问题的理想环境，我们正在完成合作研究 方案项目(CSP#575B)，在MVP的背景下，确定与以下方面相关的遗传风险因素 创伤后应激障碍及相关特征。我们的创伤后应激障碍基因组学CSP-MVP Alpha计划 非常成功地定位了基因座，到目前为止，用于创伤后应激障碍的再体验和其他相关 表型(如“最大习惯性饮酒量”)。尽管PTSD Gwas数据本身是 在分析中，仍有大量工作需要做，以充分发展和最大限度地利用 MVP作为可分析的MVP样本对创伤后应激障碍及相关表型的科学价值 继续增长。在这个项目的过程中，我们已经很好地组建了一个专家团队- 有资格继续这项工作。为了继续这项工作，我们提出了一组扩展的分析 一个更大的样本，以及GWAS之后的分析。 随着研究对象的增多，绘制相关特征图谱的能力将会增强；我们将继续 扩展样本中创伤后应激障碍及相关性状的GWA值。有很高的合并症 具有物质使用障碍特征的创伤后应激障碍；我们建议也探索肥皂水，包括酒精 依赖、阿片依赖、尼古丁依赖和其他肥皂水。 我们将研究创伤后应激障碍与相关性状之间的单基因和多基因重叠。 我们将研究与创伤后应激障碍相关的表型特征，如认知能力下降、阿尔茨海默氏症 疾病、持续性脑震荡后症状和免疫相关疾病(如克罗恩病) 疾病、类风湿性关节炎和多发性硬化症)。我们将使用 允许检验这些相关特征之间的因果关系的方法(例如，孟德尔式的 随机化，MR)。我们将完成一项创伤后应激障碍的全现象关联研究(Phewas) GWA值最高的基因(如CRHR1和其他)、创伤后应激障碍多基因风险评分(PR) 分析MVP和MR以检测与创伤后应激障碍发病相关的病因机制。 目的是使这些数据的科学价值最大化，并与 科学界，我们还将探索复制我们的发现在 与其他与电子病历有关的生物库联合体，如心理浮现网络的合作； 以及精神病学基因组学联盟创伤后应激障碍小组(我们目前参与了该小组)。 最后，MVP示例适用于在许多群体中推进工作，这些群体 普遍未得到充分研究。我们将研究与精神特征相关的AA人群遗传学， 拉美人、东亚人和南亚人，以及MVP系统中的其他人群，我们将 努力最大限度地利用来自所有人口的信息，并确定与所有人口相关的结果。

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.