Genomic Predictors of Combat Stress Vulnerability and Resilience

描述（由申请人提供）：该R 01申请提出了一项全基因组关联研究（GWAS），以探索发生创伤后应激障碍（PTSD）的风险或恢复力的遗传基础。关于解释为什么一些创伤幸存者发展为应激障碍（高达15%）而其他人没有的因素，几乎没有信息。然而，从创伤中恢复可能会受到一系列风险和弹性因素的影响，这些因素由遗传，心理，社会/文化和生物系统索引。该项目的目标是通过以下方法来确定这些因素：a）研究前瞻性评估的、系统的表型人群，以发现预测PTSD发展的因素; B）确定基因与环境的相互作用。圣地亚哥海军陆战队复原力研究（MRS）是一项正在进行的前瞻性研究，研究对象是2500名即将前往伊拉克或阿富汗作战的美国海军陆战队士兵，目的是确定预测PTSD发展的因素。每个海军陆战队员在部署前都要接受一系列社会心理、心理生理和生物生理表型的评估，然后在部署后进行纵向评估。选择收集的表型是因为它们有可能作为应激触发的疾病的“中间”表型，并且包括例如惊吓反应性、心率/血压以及HPA功能和儿茶酚胺信号传导的标志物。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PTSD发展的共同经历。因此，MRS是唯一适合于确定遗传和环境的PTSD症状发展的贡献。MRS的数据收集由国防部和退伍军人事务部资助，并将在本拟议资助期开始时完成，但R 01资金对于实施尚未资助的遗传部分至关重要。总体指导假设是，基因组变异会产生风险/易感性特征，当受到适当的环境刺激（例如战斗）的激发时，会产生创伤后应激障碍和其他压力触发的表型。具体而言，本申请旨在：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PTSD评分的关联，并测试基因与环境的相互作用，包括战斗和其他创伤暴露，3）测试遗传变异与PTSD脆弱性相关的简单生物学特征及其随时间的纵向变化的关联，从而建立和测试遗传风险评分，以及4）在其他群组中精细映射和复制发现。我们预计，从这种多方面的方法中获得的见解将提供一个独特的机会，以提高对PTSD遗传因素的理解，并为这种目前神秘和难以管理的疾病开辟新的诊断测试和治疗方法。重要的是，一个大型创伤后应激障碍队列的全基因组基因型数据尚未公开，因此这项研究将为神经精神研究界的遗传和环境影响研究产生丰富的资源。 公共卫生相关性：创伤后应激障碍（PTSD）不仅给个人带来痛苦，也给美国医疗保健系统带来沉重负担，在战斗和其他创伤暴露后发展PTSD的比率约为10- 15%。创伤后应激障碍只影响那些暴露于创伤的人，脆弱性因素知之甚少。该R 01申请旨在确定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型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.