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

• 批准号: 8305627
• 负责人: Caroline M Nievergelt
• 金额: $ 44.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/8305627
• 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

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.

描述（由申请人提供）：此R01申请提出了一项全基因组协会研究（GWAS），以探测遗传性的基础，以确定发展创伤后应激障碍（PTSD）的风险或韧性。关于因素的信息很少，这些因素可以解释为什么某些创伤幸存者会出现压力障碍（多达15％）而其他人则没有。但是，从创伤中恢复可能会受到风险和韧性因素的影响，并由遗传，心理，社会/文化和生物系统索引。该项目的目的是通过a）研究前瞻性评估的，系统地表型的人群来识别此类因素，以发现预测PTSD和b）缩进基因与环境相互作用的因素。圣地亚哥海洋弹性研究（MRS）是一项持续的，前瞻性的研究，> 2500美国海军陆战队绑定到伊拉克或阿富汗的战斗部署，目的是确定预测PTSD发展的因素。每次海洋陆战队都会在一系列心理社会，心理生理和生物生理学表型上评估预部部门，然后在驱逐后进行纵向评估。选择了收集的表型，以作为应激触发疾病的“中间”表型的潜力，包括惊吓反应性，心率/血压以及HPA功能和Catecholamine信号传导的标记。收集了有关过去创伤和儿童忽视等环境风险因素的信息，以确定可能影响PTSD发展的常见经验。因此，MRS非常适合确定对PTSD症状发展的遗传和环境贡献。 MRS的数据收集由DOD和VA资助，并将在此拟议的资金期开始完成，但是R01资金对于实施尚未获得的未资助的遗传成分至关重要。总体指导假设是，基因组变异会引起风险/敏感性特征，当通过适当的环境刺激（例如战斗）驱动时，会引起PTSD和其他压力触发的表型。具体而言，该应用的目的是：1）扫描约2500名作战受试者的整个基因组中的遗传变异。从而建立和测试遗传风险评分，以及4）在其他同类中进行精细图和复制发现。我们预计，从这种多方面的方法中获得的见解将为提高对PTSD的遗传贡献者的理解，并为这种新型诊断测试和治疗方法开辟道路，为这种当前的神秘且难以管理的状况开辟道路。重要的是，尚未公开获得大型PTSD队列的基因组 - 广泛的基因型数据，因此该研究将为神经精神病学研究界的遗传和环境影响提供丰富的资源。