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）：该提案旨在检查基因环境相互作用，这有助于从960人中从纽约大都会地区的2750名男性和女性中选择的960人开发PTSD，暴露于世界贸易中心攻击。该队列最初是在9月11日之后六个月招募的，纵向遵循，目的是确定该事件导致的心理健康后果，并且足够大，足以对这种疾病的危险因素进行全面的调查。我们将研究先前假设或证明与PTSD风险有关的临床和神经内分泌测量，与皮质醇信号的改变有关。由于遗传因素有助于该生物系统的功能，因此我们将检查与糖皮质激素活性相关的几种基因的多态性，以及与PTSD病理生理学有关的肽基因和单胺能神经传递。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查表达谱。验证的基因子集也将是与PTSD关联的基因分型。此外，基于最近证明与PTSD相关的PTSD和皮质醇改变的非遗传间传播的证据（即，从具有创伤的父母患有PTSD的父母到其后代），我们将检查基因活性的稳定个体差异，这些差异是通过经验来通过经验来通过经验来通过表皮机制（E.G. e.g.，e.g.，dna甲基化的）进行“进行编程”。这些研究将集中在淋巴细胞中糖皮质激素受体（GR）的特定启动子区域，该组织证明对PTSD中的糖皮质激素反应更敏感。因此，将有可能将“遗传和非遗传危险因素和与创伤严重程度的相互作用”与GR启动子部位的DNA甲基化的表观遗传变化联系起来，以理解简单的问题，但尚未确定创伤在PTSD发展中的创伤作用以及在PTSD发展中的作用，以及在PTSD发展中的某些人而不是PTS的唯一范围，而不是PTS的独特之处。同时，与这个多机构的团队中所反映的专业知识将提供有关PTSD的分子遗传基础，PTSD脆弱性和压力抗性的明确信息：与公共卫生相关。以及对遗传或早期环境影响的差异的强调，这使一些更脆弱。仅在了解个人风险因素及其与事件暴露的相互作用后，才能发生预防和治疗模型的发展模型。