Genomic Predictors of Combat Stress Vulnerability and Resilience

描述(由申请人提供)：这份R01申请提出了一项全基因组关联研究(GWAS)，以探索患创伤后应激障碍(PTSD)的风险或弹性的遗传基础。关于为什么一些创伤幸存者会患上应激障碍(高达15%)，而其他人不会的原因，几乎没有相关信息。然而，创伤后的恢复可能受到一系列风险和复原力因素的影响，这些因素以遗传、心理、社会/文化和生物系统为索引。该项目的目标是通过a)研究前瞻性评估的、系统的表型人群，以发现预测创伤后应激障碍发展的因素，以及b)确定基因与环境的相互作用来确定这些因素。圣地亚哥海军陆战队复原力研究(MRS)是一项持续的、前瞻性的研究，对2500名将被部署到伊拉克或阿富汗作战的美国海军陆战队士兵进行研究，目的是确定预测创伤后应激障碍发展的因素。每名海军陆战队士兵在部署前都要对一系列心理社会、心理生理学和生物生理学表型进行评估，然后在部署后进行纵向评估。收集的表型是因为它们有可能作为应激触发障碍的“中间”表型，包括例如惊吓反应、心率/血压、HPA功能和儿茶酚胺信号的标记。收集有关环境风险因素的信息，如过去的创伤和童年忽视，以确定可能影响创伤后应激障碍发展的共同经历。因此，MRS特别适合于确定遗传和环境因素对创伤后应激障碍症状发展的影响。MRS的数据收集由国防部和退伍军人事务部提供资金，并将在本拟议资助期开始时完成，但R01的资金对于实施尚未获得资金的遗传部分至关重要。总体的指导性假设是，基因组变异会产生风险/易感特征，当受到适当的环境刺激(如战斗)激励时，这些特征会产生创伤后应激障碍和其他应激触发的表型。具体地说，该应用程序的目标是：1)扫描约2500名战斗暴露受试者的整个基因组以寻找遗传变异，2)检查遗传变异与创伤后应激障碍评分的关联，并测试基因与环境的交互作用，包括战斗和其他创伤暴露，3)测试遗传变异与与创伤后应激障碍脆弱性及其随时间的纵向变化有关的更简单的生物学特征的关联，从而建立和测试遗传风险评分，以及4)精细绘制并复制其他队列中的发现。我们预计，从这种多方面的方法获得的见解将提供一个独特的机会，以提高对创伤后应激障碍的遗传因素的了解，并为这种目前神秘且难以管理的疾病开辟新的诊断测试和治疗方法。重要的是，大规模创伤后应激障碍队列的全基因组基因数据尚未公开，因此这项研究将为神经精神病学研究界提供丰富的遗传和环境影响研究资源。 公共卫生相关性：创伤后应激障碍(PTSD)不仅对个人造成痛苦，而且对美国医疗体系构成重大负担，战后和其他创伤暴露后患PTSD的比率约为10%-15%。创伤后应激障碍只会影响那些暴露在创伤中的一些人，而且对易感性因素了解很少。这一R01应用程序寻求确定PTSD临床结果的遗传贡献和预测因素，从而为这种难以管理的疾病的新诊断测试和治疗方法铺平道路。

DESCRIPTION (provided by applicant): This R01 application proposes a genome-wide association study (GWAS) to probe the hereditary basis for risk or resilience to develop post-traumatic stress disorder (PTSD). Little information is available about factors that explain why some trauma survivors develop stress disorders (up to 15%) and others do not. However, recovery from trauma may be impacted by a web of risk and resilience factors, indexed by genetic, psychological, social/cultural, and biological systems. The goal of this project is to identify such factors by a) studying a prospectively assessed, systematically phenotyped population to discover factors that predict development of PTSD and b) indentifying gene-by-environment interactions. The San Diego Marine Resiliency Study (MRS) is an ongoing, prospective study of >2500 US Marines bound for combat deployment to Iraq or Afghanistan, with the goal to identify factors that predict development of PTSD. Each Marine is evaluated pre-deployment on an array of psychosocial, psychophysiological, and biophysiological phenotypes, and then followed by longitudinal assessments post-deployment. The phenotypes collected were chosen for their potential to serve as 'intermediate' phenotypes for stress-triggered disorders, and include for example startle reactivity, heart rate/blood pressure, and markers of HPA function and catecholamine signaling. Information on environmental risk factors such as past trauma and childhood neglect are collected to identify common experiences that may influence PTSD development. The MRS is thus uniquely suited to identify both genetic and environmental contributions to PTSD symptom development. Data collection of the MRS is funded by the DoD and VA, and will be completed at the start of this proposed funding period, but R01 funding is essential for the implementation of the as-yet un-funded genetic component. The overall guiding hypothesis is that genomic variations give rise to risk/susceptibility traits that, when actuated by the appropriate environmental stimulus, such as combat, give rise to PTSD and other stress- triggered phenotypes. Specifically, this application aims to: 1) Scan the entire genome of ~2500 combat- exposed subjects for genetic variants, 2) Examine the association of genetic variants with PTSD scores, and test for gene-by-environment interactions including combat and other trauma exposure, 3) Test for association of genetic variants with simpler biological traits linked to PTSD vulnerability and its longitudinal changes over time, and thus to build and test genetic risk scores, and 4) Fine-map and replicate findings in other cohorts. We anticipate that the insights gained from this multi-faceted approach will provide a unique opportunity to improve understanding of the genetic contributors to PTSD, and open the way towards novel diagnostic tests and therapeutic approaches to this currently enigmatic and difficult-to-manage condition. Importantly, genome- wide genotype data of a large PTSD cohort is not yet publicly available, and this study thus will generate a rich resource for research on genetic and environmental effects for the neuropsychiatric research community. PUBLIC HEALTH RELEVANCE: Post-traumatic stress disorder (PTSD) poses not only individual suffering, but also a significant burden on the US health care system, with rates to develop PTSD after combat and other trauma exposure around 10-15%. PTSD affects only some of those exposed to trauma, and vulnerability factors are poorly understood. This R01 application seeks to determine genetic contributions to and predictors of the clinical outcome of PTSD, and thus to pave the way for novel diagnostic tests and therapeutic approaches to this difficult-to-manage disorder.