Genetics, Endocrinology and PTSD Risk in the Population

描述（由申请人提供）：本提案旨在研究基因-环境相互作用对960人PTSD发展的影响，这些人是从纽约大都会区暴露于世贸中心袭击事件的2750名男性和女性中挑选出来的。这个队列最初是在9 / 11事件发生六个月后招募的，为了确定这一事件对心理健康的影响，已经进行了纵向跟踪，而且规模足够大，可以对这种疾病的风险因素进行全面调查。我们将检查先前假设或证明与PTSD风险相关的临床和神经内分泌指标，这些指标与皮质醇信号的改变有关。由于遗传因素影响了这一生物系统的功能，我们将研究与糖皮质激素活性相关的几个基因的多态性，以及与PTSD病理生理相关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查表达谱。被验证的基因子集也将被基因分型以确定与创伤后应激障碍的关联。此外，基于最近关于创伤后应激障碍的非遗传代际传播和与创伤后应激障碍相关的皮质醇改变的证据（即，从创伤暴露的创伤后应激障碍父母到他们的后代），我们将研究基因活性的稳定个体差异，这些差异受表观遗传机制（例如，DNA甲基化）的经验“编程”影响。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，该组织被证明对创伤后应激障碍的糖皮质激素更敏感。因此，有可能将GR启动子位点DNA甲基化的表观遗传改变与“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得到解答的问题，以及更复杂的一个问题，即为什么有些人在创伤暴露后患上PTSD，而另一些人却没有。这一独特而具有代表性的队列的巧合，以及这个多机构团队所反映的专业知识，将提供关于创伤后应激障碍、创伤后应激障碍易感性和应激抵抗的分子遗传基础的明确信息。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PTSD，而大多数人不会，这方面的知识存在重大差距。造成这种差异的原因是过分强调创伤后应激障碍是对事件的反应，而对基因或早期环境影响的差异重视不足，这些影响使一些人更容易受到伤害。只有在了解个体风险因素及其与事件暴露的相互作用之后，才能开发出预防和治疗创伤后应激障碍的模型。

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.