Genetic and Trauma-Related Risk Factors for PTSD

描述（由申请人提供）：本项目将在一项高度创伤、低社会经济地位、少数民族人群的横断面研究中确定创伤后应激障碍（PTSD）的遗传和创伤相关风险因素的相对贡献。虽然某种程度的恐惧和压力在创伤经历后是正常的，但一个关键的问题是，为什么并非所有经历创伤的人都出现慢性病理症状。个体在创伤应激反应中似乎有不同的脆弱性。创伤后应激障碍很可能是由易感遗传和环境风险的相互作用造成的，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，基因对创伤后应激障碍的影响以及它们如何与其他风险因素相互作用几乎一无所知。我们将检查来自亚特兰大格雷迪纪念医院综合医学诊所的1000名非精神病患者。我们的试点数据显示，超过80%的人遭受过严重的创伤，大约30%的人患有创伤后应激障碍。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、创伤终生史和创伤后应激相关事件的创伤周围情绪反应。遗传风险因素包括在其他压力相关精神疾病的发展中描述的多态性，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）。终生创伤史包括童年创伤史和终生创伤史。对创伤的情绪反应包括主观的严重程度以及创伤前后的分离。要检查的协变量包括家族精神病史、药物滥用/依赖和共病精神诊断。主要的因变量包括是否有PTSD诊断及其严重程度。创伤后应激障碍是一种具有症状变异的复杂疾病。在其他复杂疾病中成功的遗传关联研究依赖于对特定特征或“内表型”的分析，这些特征或“内表型”包括疾病的不同方面。因此，本研究还将研究PTSD的二级依赖特征变量或内表型：1)侵入性、高唤醒性和回避性症状；2) HPA失调的生理指标（皮质醇和ACTH基线，经dex-抑制和dex-CRH测试）；3)基线声惊和暗增强声惊的评估。通过研究已确定的候选基因、创伤史、创伤后应激障碍诊断及其组成特征，本研究将进一步了解创伤后应激障碍。通过对创伤后导致病理性恐惧和压力的遗传和环境因素的更深入了解，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.