Genetics, Endocrinology and PTSD Risk in the Population

人群中的遗传学、内分泌学和创伤后应激障碍风险

• 批准号: 7087364
• 负责人: RACHEL YEHUDA
• 金额: $ 20万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-10 至 2008-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087364
• 关键词: behavioral /social science research tag; biotechnology; clinical research; corticosteroid receptors; cortisol; disasters; epigenetics; gene environment interaction; gene expression profiling; genetic markers; genetic polymorphism; genetic promoter element; genetic susceptibility; glucocorticoids; human genetic material tag; human subject; longitudinal human study; lymphocyte; mental health epidemiology; microarray technology; polymerase chain reaction; posttraumatic stress disorder; psychopathology; social psychology; violence

DESCRIPTION (provided by applicant): This proposal seeks to examine gene-environment interactions that contribute to the development of PTSD in 960 persons selected from a well-characterized sample of 2750 men and women in the New York metropolitan area, exposed to the World Trade Center attacks. This cohort was initially recruited six months after September 11th, has been followed longitudinally for the purpose of determining mental health consequences resulting from this event, and is sufficiently large enough to undertake a comprehensive investigation of risk factors for this disorder. We will examine clinical and neuroendocrine measures previously hypothesized or demonstrated to be associated with risk for PTSD, related to alterations in cortisol signaling. Since genetic factors contribute to the function of this biological system, we will examine polymorphisms of several genes related to glucocorticoid activity, as well as peptidergic and monoaminergic neurotransmission implicated in PTSD pathophysiology. To determine the involvement of other relevant genes, we will examine expression profiles using microarray techniques and quantitative polymerase chain reaction. The subset of genes that are validated will also be genotyped for association with PTSD. Additionally, based on recent evidence for non-genetic intergenerational transmission of PTSD and cortisol alterations associated with PTSD (i.e., from trauma-exposed parents with PTSD to their offspring), we will examine stable individual differences in gene activity that are subject to 'programming' by experience via epigenetic mechanisms (e.g., DNA methylation). These studies will focus on specific promoter regions of the glucocorticoid receptor (GR) in lymphocytes, a tissue demonstrated to be more responsive to glucocorticoids in PTSD. It will therefore be possible to associate epigenetic alterations in DNA methylation at GR promoter sites with" genetic and non-genetic risk factors, and their interaction with trauma severity, towards the aim of understanding the simple, but as yet unanswered question of the role of trauma in the development of PTSD, and the even more complex one of why some persons develop PTSD following trauma exposure while others do not. The coincidence of this unique and representative cohort, together with the expertise reflected in this multi-institutional team, will provide unambiguous information concerning the molecular- genetic basis of PTSD, PTSD vulnerability, and stress resistance. Relevance to Public Health: There is a major gap in knowledge regarding why only some exposed to trauma develop PTSD, while the majority do not. This gap results from an over-emphasis on PTSD as a response to an event and an under-emphasis on differences in genetic or early environmental influences that make some more vulnerable. The development of models of prevention and treatment of PTSD can only occur following an understanding of individual risk factors and their interactions with event exposure.

描述（由申请人提供）：该提案旨在研究基因-环境相互作用，这些相互作用有助于从纽约大都市区暴露于世贸中心袭击的2750名男性和女性的良好表征样本中选出的960人患上PTSD。该队列最初是在9月11日之后6个月招募的，为了确定该事件导致的心理健康后果，已经进行了纵向跟踪，并且足够大，足以对这种疾病的风险因素进行全面调查。我们将检查临床和神经内分泌措施，以前假设或证明与创伤后应激障碍的风险，皮质醇信号的改变有关。由于遗传因素有助于这个生物系统的功能，我们将研究与糖皮质激素活性相关的几个基因的多态性，以及PTSD病理生理学中涉及的肽能和单胺能神经传递。为了确定其他相关基因的参与，我们将使用微阵列技术和定量聚合酶链反应检测表达谱。被验证的基因子集也将被基因分型为与PTSD相关。此外，根据最近关于PTSD的非遗传代际传递和与PTSD相关的皮质醇改变的证据（即，从患有创伤后应激障碍的创伤暴露父母到他们的后代），我们将检查基因活性的稳定个体差异，这些差异通过表观遗传机制（例如，DNA甲基化）。这些研究将集中在淋巴细胞中糖皮质激素受体（GR）的特异性启动子区域，淋巴细胞是一种对PTSD中糖皮质激素反应更敏感的组织。因此，有可能将GR启动子位点DNA甲基化的表观遗传学改变与”遗传和非遗传风险因素，以及它们与创伤严重程度的相互作用“联系起来，以理解创伤在PTSD发展中的作用这一简单但尚未回答的问题，以及为什么有些人在创伤暴露后发展为PTSD而另一些人则没有的更复杂的问题。这个独特的和代表性的队列的巧合，以及在这个多机构的团队中反映的专业知识，将提供有关PTSD的分子遗传基础，PTSD的脆弱性，和压力抵抗力的明确信息。与公共卫生的相关性：关于为什么只有一些暴露于创伤的人会患上创伤后应激障碍，而大多数人不会，在知识上存在重大差距。这种差距是由于过度强调创伤后应激障碍是对事件的反应，而不重视遗传或早期环境影响的差异，这些差异使一些人更容易受到伤害。PTSD的预防和治疗模式的发展只能发生在理解个体风险因素及其与事件暴露的相互作用之后。