Genomics of PTSD and Related Traits

摘要 创伤后应激障碍（PTSD）是退伍军人的一个主要问题，但 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)是研究这个问题的理想环境，我们正在完成一项合作研究， 在MVP背景下的计划项目（CSP#575B），以确定与以下相关的遗传风险因素： PTSD及相关症状我们的创伤后应激障碍基因组学CSP-MVP Alpha项目已经 非常成功地绘制基因位点，到目前为止，对于PTSD的再体验和其他相关的 表型（如“最大习惯性饮酒”）。虽然PTSD GWAS数据本身 根据分析，仍然需要做大量的工作，以充分发展和最大限度地发挥 作为可分析MVP样本，MVP对PTSD和相关表型的科学价值 一个继续增长在这个项目的过程中，我们组建了一个很好的专家团队- 有资格继续工作。为了继续这项工作，我们提出了一套扩展分析， 更大的样本和GWAS后的分析。 随着更多的受试者，绘制相关特征的能力将增加;我们将继续 扩大样本中PTSD和相关特征的GWAS。有很高的协方差系数， 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，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 允许测试这些相关性状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鉴定的最高基因（例如，CRHR 1和其他），PTSD多基因风险评分（PRS） MVP和MR中的分析，以检测与PTSD发病机制相关的因果机制。 为了最大限度地发挥这些数据的科学价值，并与 科学界，我们还将探讨复制我们的研究结果的可能性， 与其他与EHR相关的生物库联盟合作，如Psych-EMERGE网络; 以及精神病学基因组学联盟PTSD小组（我们目前参与其中）。 最后，MVP样本适合于在许多人群中推进工作， 一般来说，研究。我们将研究AA的精神病学特征相关群体遗传学， 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 努力最大限度地利用来自所有人群的信息，并确定与所有人群相关的结果。

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.