Genomic Predictors of Combat Stress Vulnerability and Resilience

战斗压力脆弱性和恢复力的基因组预测因子

基本信息

批准号：
8083919
负责人：
Caroline M Nievergelt
金额：
$ 180.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-25 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8083919
关键词：
Affect Afghanistan African American Alcohol abuse Anxiety Area Asians Binding Biological Blood Pressure Catecholamines Clinical Cohort Studies Communities Complex Cross-Sectional Studies Data Data Collection Development Diagnostic tests Disease Environment Environmental Risk Factor Evaluation Exposure to Funding Genes Genetic Genetic Risk Genome Genomics Genotype Goals Healthcare Systems Heart Rate Hispanics Home environment Individual Inherited Internet Iraq Link Maps Marines Measures Mental Depression Modeling Molecular Outcome Penetrance Phenotype Physiological Population Post-Traumatic Stress Disorders Predisposition Prospective Studies Psychopathology Psychophysiology Research Research Design Resources Risk Scanning Secure Signal Transduction Stimulus Stress Survivors Symptoms Syndrome System Testing Therapeutic Time Trauma Trauma recovery Traumatic Stress Disorders Variant War base biological systems case control clinical phenotype cohort combat experience follow-up gene environment interaction genetic variant genome wide association study genome-wide genome-wide analysis improved indexing insight interest longitudinal design neglect neuropsychiatry novel diagnostics pediatric trauma prospective psychologic psychosocial resilience social stress related disorder trait

项目摘要

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.

描述（由申请人提供）：此 R01 申请提出了一项全基因组关联研究 (GWAS)，以探讨患创伤后应激障碍 (PTSD) 的风险或恢复力的遗传基础。关于为什么一些创伤幸存者会出现应激障碍（高达 15%）而其他幸存者则不会的因素，我们所知甚少。然而，从创伤中恢复可能会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以下方式确定这些因素：a) 研究前瞻性评估、系统表型的人群，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) 是一项持续的前瞻性研究，对象是超过 2500 名前往伊拉克或阿富汗作战的美国海军陆战队员，目的是确定预测 PTSD 发展的因素。每名海军陆战队员在部署前都会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。选择收集的表型是因为它们有可能作为应激引发的疾病的“中间”表型，包括惊吓反应性、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（例如过去的创伤和童年忽视）的信息，以确定可能影响 PTSD 发展的常见经历。因此，MRS 特别适合识别遗传和环境对 PTSD 症状发展的影响。 MRS 的数据收集由国防部和退伍军人管理局资助，并将在本拟议资助期开始时完成，但 R01 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）驱动时，会引起创伤后应激障碍（PTSD）和其他压力引发的表型。具体来说，该应用程序旨在：1) 扫描约 2500 名经历过战斗的受试者的整个基因组，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) 测试遗传变异与与 PTSD 脆弱性及其随时间的纵向变化相关的更简单的生物特征的关联，从而建立和测试遗传风险评分，以及 4) 在其他队列中精细绘制和复制研究结果。我们预计，从这种多方面的方法中获得的见解将为增进对 PTSD 遗传因素的理解提供独特的机会，并为针对这种目前神秘且难以管理的疾病的新型诊断测试和治疗方法开辟道路。重要的是，大型 PTSD 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。公共健康相关性：创伤后应激障碍 (PTSD) 不仅给个人带来痛苦，而且给美国医疗保健系统带来重大负担，在战斗和其他创伤暴露后患上 PTSD 的比率约为 10-15%。创伤后应激障碍（PTSD）仅影响部分遭受创伤的人，而人们对脆弱性因素知之甚少。该 R01 应用旨在确定 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诊断测试和治疗方法铺平道路。