Identification of an Epigenetic Risk Marker for PTSD

描述（由申请人提供）：该补助金响应NIH挑战08-MH-103：了解精神疾病的基因组风险结构。这项应用建立在最近的动物和人类数据的表观遗传机制介导的“糖皮质激素编程”，以解决知识的关键差距如何早期的经验赋予增加的生物风险创伤后应激障碍（PTSD）。知识上的差距将通过检查糖皮质激素受体（GR）基因的胞嘧啶甲基化来解决。与PTSD风险相关的表观遗传修饰的研究代表了一个重要的科学前沿。创伤后应激障碍只发生在一部分暴露于创伤的人中，但人群终身患病率为10- 14%。母亲PTSD已被确定为第二代后代（F2）PTSD的风险因素，允许检查与此风险因素相关的生物学机制。GR基因是研究的焦点，因为反映GR反应性增强的改变已在患有母亲PTSD的F2和其他PTSD样本中得到证实。（GR敏感性，负反馈抑制，基础皮质醇水平和代谢）将在120名大屠杀幸存者的F2（根据是否存在母亲和父亲PTSD分组）和30名没有父母大屠杀暴露或PTSD的受试者中进行检查。由于糖皮质激素编程也被认为是一种机制，通过这种机制，[在子宫内]母体压力增加了成年后代随后发生代谢综合征（MetS）的风险，最近的数据将PTSD与MetS的发展及其后果联系起来，因此也将获得MetS的数据。该项目可以在两年内完成，因为我们可以从之前研究过的同意重新联系的Holocaust F2中招募人员。将使用Michael Meaney，Ph.D.开发的聚合酶链反应（PCR）引物定量胞嘧啶甲基化。选择性扩增GR基因相关区域的变异，用于人淋巴细胞中mRNA的DNA甲基化和剪接变体分析。Meaney博士的研究小组已经证实，人类GR基因的组织与大鼠GR非常相似。我们的主要假设是，与父亲相比，母亲的PTSD在F2中的胞嘧啶甲基化程度更高。路径分析模型将研究这种表观遗传修饰对与PTSD风险相关的神经内分泌和代谢后果的贡献，并结合早期生活经历的其他相关方面（父母症状，儿童虐待和忽视，父母照顾和过度保护）来评估其贡献。这项工作是创新的，试图使用一个自然的代际“模型系统”，以检查的作用，在PTSD和相关的健康风险的传播脆弱性的表观遗传机制，并确定其与其他环境因素的关系。这些结果对检测有PTSD风险的人有意义，但也可能指向预防和早期治疗的新目标。患有创伤后应激障碍（PTSD）的母亲的成年子女患PTSD的风险增加，并且他们对应激激素皮质醇的反应性也发生变化，这似乎反映了早期发育的影响，可能是由母亲的压力影响造成的。在这项研究中，我们调查了这些后代的生物学变化是否反映了一种持久的表观遗传修饰，这种修饰是由早期母体行为引起的，这种行为导致皮质醇系统的“重新校准”，从而增加了随后的创伤后应激障碍和其他健康后果的风险。如果观察到这种变化，这项研究将产生一个早期（即，创伤前）生物标志物，其最终可用于在暴露于创伤之前或之后立即筛查PTSD风险增加的人。

DESCRIPTION (provided by applicant): This grant responds to NIH Challenge 08-MH-103: Understanding the Genomic Risk Architecture of Mental Disorders. This application builds on recent animal and human data on epigenetic mechanisms mediating 'glucocorticoid programming' to address a critical gap in knowledge about how early experience confers increased biological risk for post-traumatic stress disorder (PTSD). The gap in knowledge will be addressed by examining cytosine methylation of the glucocorticoid receptor (GR) gene. The study of epigenetic modifications in relation to PTSD risk represents an important scientific frontier. PTSD occurs in only a proportion of those exposed to trauma, but has a population lifetime prevalence of 10-14%. Maternal PTSD has been identified as a risk factor for PTSD in 2nd generation offspring (F2) allowing examination of biological mechanisms in association with this risk factor. The GR gene is the focus of investigation because alterations reflecting enhanced GR responsiveness have been demonstrated in F2 with maternal PTSD, and in other PTSD samples.The relationships among cytosine methylation, GR gene expression, and neuroendocrine measures associated with PTSD risk (GR sensitivity, negative feedback inhibition, basal cortisol level and metabolism) will be examined in 120 F2 of Holocaust survivors (grouped by presence or absence of maternal and paternal PTSD) and in 30 subjects with no parental Holocaust exposure or PTSD. Since glucocorticoid programming has also been implicated as a mechanism through which [in utero] maternal stress increases risk for the subsequent development of metabolic syndrome (MetS) in their adult offspring, and recent data have linked PTSD to the development of MetS and its consequences, data on MetS will also be obtained. This project can be accomplished in two years because we can recruit from previously studied Holocaust F2 that agreed to be recontacted. Cytosine methylation will be quantified using polymerase chain reaction (PCR) primers developed by Michael Meaney, Ph.D. that selectively amplify variations in the relevant region of the GR gene for DNA methylation and splice variant analysis of mRNA in the human lymphocyte. Dr. Meaney's group has confirmed that the organization of the human GR gene closely resembles the rat GR. Our primary hypothesis is that cytosine methylation will be greater in F2 with maternal than paternal PTSD. A path analysis model will examine the contribution of this epigenetic modification to neuroendocrine and metabolic consequences associated with PTSD risk, incorporating other relevant aspects of early life experience (parental symptoms, childhood abuse and neglect, parental care and overprotection) to assess their contribution. This work is innovative in attempting to use a naturalistic intergenerational 'model system' to examine the role for an epigenetic mechanism in transmitted vulnerability for PTSD and associated health risks, and determine their relationship to other environmental contributors. The results have implications for detecting persons at risk for PTSD, but may also point to novel targets for prophylaxis and early treatment. Adult children of mothers with post traumatic stress disorder (PTSD) are at increased risk for PTSD, and also show changes in their responsiveness to the stress hormone cortisol that appear to reflect early developmental influences, possibly resulting from maternal stress effects. In this grant we investigate whether the biological changes in these offspring reflect an enduring epigenetic modification, induced by early maternal behavior that resulted in 'recalibrating' the cortisol system in a manner that increases risk for subsequent PTSD and possibly other health consequences. If such changes are observed, this research will yield an early (i.e., pretraumatic) biologic marker that can ultimately be used in screening persons at increased risk for PTSD either before or immediately after they are exposed to trauma.