Genetic and Trauma-Related Risk Factors for PTSD

描述(由申请人提供)：这个项目将在一项对高度创伤、低社会经济地位的少数族裔人口的横断面研究中，确定遗传和创伤相关风险因素对创伤后应激障碍(PTSD)的相对贡献。虽然在经历创伤后产生一定程度的恐惧和压力是正常的，但一个关键的问题是，为什么所有经历过创伤的人都不会出现慢性病理症状。每个人在创伤应激反应中似乎都有不同的脆弱性。创伤后应激障碍很可能是易感性遗传和环境风险相互作用的结果，这些风险增加了严重创伤后发生病理性应激反应和恐惧记忆的可能性。然而，对于创伤后应激障碍的遗传因素(S)的性质以及它们如何与其他风险因素相互作用，人们几乎一无所知。我们将检查来自亚特兰大格雷迪纪念医院普通医疗诊所的1000名非精神病人。我们的试点数据表明，超过80%的人遭受过严重的创伤，约30%的人患有创伤后应激障碍。我们将研究影响创伤后创伤后应激障碍相对风险的独立因素：基因多态、创伤终生病史以及创伤后相关事件的创伤前后情绪反应。遗传风险因素包括在其他应激相关精神障碍的发展过程中已被描述的多态，包括单胺相关基因(5HTT、DBH、DAT和COMT)、脑源性神经营养因子(BDNF)和参与HPA轴调节的基因(GR、CRF-R1、FKBP5)。一生创伤史包括童年创伤和终生创伤。对创伤的情绪反应包括主观严重程度和创伤周围的分离。要检查的协变量包括家庭精神病史、药物滥用/依赖和共病精神诊断。主要因变量包括有无创伤后应激障碍诊断及其严重程度。创伤后应激障碍是一种复杂的疾病，具有症状变体。在其他复杂疾病中，成功的遗传关联研究依赖于对构成疾病不同方面的特定特征或“内表型”的分析。因此，这项研究还将检查创伤后应激障碍的次级依赖性状变量或内表型：1)侵入性、高度觉醒和回避性症状；2)HPA失调的生理标记物(Dex抑制和Dex-CRH测试后基线的皮质醇和ACTH)；以及3)基线和黑暗增强的声音惊吓的评估。通过研究已确定的候选基因、创伤病史、创伤后应激障碍的诊断以及其组成部分特征，本研究将进一步加深对创伤后应激障碍的理解。通过更好地了解导致创伤后病理性恐惧和压力的遗传和环境因素，这项工作将进一步发展模型系统，并有可能为这种衰弱障碍提供新的干预、诊断和治疗方法。

DESCRIPTION (provided by applicant): This project will determine the relative contribution of genetic and trauma-related risk factors for Posttraumatic Stress Disorder (PTSD) in a cross-sectional study of a highly traumatized, low socioeconomic status, minority population. Although some level of fear and stress is normal following a traumatic experience, a critical question is why chronic pathological symptoms do not occur in all who experience trauma. Individuals appear to have different vulnerabilities in their traumatic stress response. It is likely that PTSD results from an interaction of predisposing genetic and environmental risks that enhance the likelihood of a pathological stress response and fear memory following severe trauma. However, almost nothing is known of the nature of the genetic contribution(s) to PTSD and how they interact with other risk factors. We will examine 1000 non-psychiatric patients from the General Medical Clinic at Grady Memorial Hospital in Atlanta. Our pilot data suggests that over 80% of this population has suffered significant trauma and approximately 30% have PTSD. We will examine independent factors that contribute to the relative risk for PTSD following trauma: genotype polymorphism, lifetime history of trauma, and peri-traumatic emotional response to the PTSD-related event. Genetic risk factors include polymorphisms that have been described in the development of other stress-related psychiatric disorders, including monoamine related genes (5HTT, DBH, DAT, and COMT), brain-derived neurotrophic factor (BDNF), and genes involved in HPA axis regulation (GR, CRF-R1, FKBP5). Lifetime history of trauma includes childhood trauma and total lifetime trauma. Emotional response to trauma includes subjective severity as well as peri-traumatic dissociation. Covariates to be examined include family psychiatric history, substance abuse / dependence, and comorbid psychiatric diagnoses. The primary dependent variables include presence or absence of PTSD diagnosis and its severity. PTSD is a complex disorder with symptomatic variants. Successful genetic association studies in other complex disorders have relied upon analysis of specific traits, or 'endophenotypes', that comprise separate aspects of the disorder. Therefore, this study will also examine secondary dependent trait variables, or endophenotypes of PTSD:1)intrusive, hyperarousal, and avoidant symptoms; 2) physiological markers of HPA dysregulation (cortisol and ACTH at baseline, after dex-suppression and dex-CRH tests); and 3) assessment of baseline and dark-enhanced acoustic startle. By examining identified candidate genes, trauma history, and PTSD diagnosis as well as its component traits, this study will further the understanding of PTSD. Through a greater understanding of the vulnerability factors, both genetic and environmental, that contribute to pathological fear and stress following a trauma, this work will further the development of model systems as well as potentially provide novel intervention, diagnostic, and treatment approaches for this debilitating disorder.