Genomic Predictors of Combat Stress Vulnerability and Resilience

描述（由申请人提供）：本R01申请提出了一项全基因组关联研究（GWAS），以探索创伤后应激障碍（PTSD）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会患上应激障碍（高达15%）而另一些人不会的因素的信息很少。然而，从创伤中恢复可能受到一系列风险和恢复力因素的影响，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a)研究前瞻性评估，系统表型人群，以发现预测PTSD发展的因素，b)确定基因与环境的相互作用，来确定这些因素。圣地亚哥海洋弹性研究（MRS）是一项正在进行的前瞻性研究，研究对象是即将被部署到伊拉克或阿富汗作战的2500名美国海军陆战队员，目的是确定预测PTSD发展的因素。每个陆战队员在部署前都要接受一系列心理社会、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。收集到的表现型被选择为应激引发疾病的“中间”表现型，包括惊吓反应性、心率/血压、HPA功能和儿茶酚胺信号标记。收集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是唯一适合于确定PTSD症状发展的遗传和环境因素的方法。MRS的数据收集由国防部和VA资助，并将在拟议的资助期开始时完成，但R01资金对于实施尚未获得资助的基因部分至关重要。总体的指导假设是，基因组变异会产生风险/易感性特征，当这些特征被适当的环境刺激（如战斗）激活时，会产生创伤后应激障碍和其他应激引发的表型。具体而言，此应用程序旨在：1)扫描约2500名战斗暴露受试者的全基因组，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相互作用，包括战斗和其他创伤暴露；3)测试遗传变异与创伤后应激障碍易感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；4)在其他队列中精细绘制和重复研究结果。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，以提高对创伤后应激障碍遗传因素的理解，并为这种目前神秘而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病学研究界的遗传和环境影响研究提供丰富的资源。

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.