Genetic and Trauma-Related Risk Factors for PTSD

描述（由申请人提供）：该项目将确定遗传和创伤相关的风险因素对创伤后应激障碍（PTSD）的相对贡献，在一个高度创伤，低社会经济地位的少数民族人口的横断面研究中。虽然在创伤经历后，一定程度的恐惧和压力是正常的，但一个关键问题是为什么慢性病理症状不会发生在所有经历创伤的人身上。个体在创伤应激反应中似乎有不同的脆弱性。PTSD很可能是由易感基因和环境风险的相互作用引起的，这些风险增加了严重创伤后病理性应激反应和恐惧记忆的可能性。然而，几乎没有人知道PTSD的遗传贡献的性质以及它们如何与其他风险因素相互作用。我们将检查1000名来自亚特兰大格雷迪纪念医院普通医疗诊所的非精神病患者。我们的试点数据表明，超过80%的这一人群遭受了严重的创伤，约30%有创伤后应激障碍。我们将研究导致创伤后PTSD相对风险的独立因素：基因型多态性，一生的创伤史，以及创伤前后对PTSD相关事件的情绪反应。遗传风险因素包括在其他应激相关精神疾病的发展中描述的多态性，包括单胺相关基因（5 HTT，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，FKBP 5）。终生创伤史包括童年创伤和终生创伤。创伤的情绪反应包括主观严重程度和创伤前后的分离。待检查的协变量包括家族精神病史、药物滥用/依赖和共病精神病诊断。主要因变量包括是否存在PTSD诊断及其严重程度。创伤后应激障碍是一种复杂的疾病，有症状的变体。在其他复杂疾病中成功的遗传关联研究依赖于对特定性状或“内表型”的分析，这些性状或“内表型”包括疾病的不同方面。因此，本研究还将检查次要依赖性特质变量，或PTSD的内表型：1）侵入性、过度觉醒和回避症状; 2）HPA失调的生理标志物（基线时的皮质醇和ACTH，dex抑制和dex-CRH测试后）; 3）基线和黑暗增强声惊吓的评估。本研究通过对已确定的候选基因、创伤史、创伤后应激障碍诊断及其组成特征的研究，将进一步加深对创伤后应激障碍的理解。通过更好地了解脆弱性因素，包括遗传和环境因素，这些因素会导致创伤后的病理性恐惧和压力，这项工作将进一步发展模型系统，并可能为这种使人衰弱的疾病提供新的干预，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.