Genetic and Epigenetic Biomarkers of PTSD

创伤后应激障碍(PTSD)是一种严重的精神障碍，发生在对 创伤性事件。在这个项目中，我们将研究DNA甲基化，一种表观遗传形式的基因调控，以 与创伤后应激障碍有关。我们将利用来自最先进的甲基化芯片的数据，这些芯片测量的数据超过 基因组上有850,000个位置。首先，我们将进行表观基因组范围的关联研究 血液中的创伤后应激障碍。接下来将对创伤后应激障碍和糖皮质激素反应的候选基因进行分析。 基于我们最近对创伤后应激障碍的全基因组基因表达研究(Logue等人，2015年)。那项研究 发现其在血液中的表达与PTSD病例/对照状态密切相关的基因，包括许多 糖皮质激素反应基因，以前没有研究过与创伤后应激障碍的关系。这些 分析将使用来自美国退伍军人事务部(VA)的两个队列(总计1000人)的数据 主要是患有创伤后应激障碍的美国退伍军人。这些调查结果的复制将从 大型表观遗传学联盟。然后，我们将进行全基因组和候选基因关联研究 使用从最近成立的创伤后应激障碍脑库获得的50个大脑组织的创伤后应激障碍。我们将具体地 分析与创伤后应激障碍有关的海马体、杏仁核和下丘脑的甲基化， HPA轴功能和焦虑。创伤后应激障碍相关差异甲基化对基因表达的影响 将使用显色原位杂交法进行研究，这将提供一种基因测量方法 并将该表达定位于特定的细胞类型(如神经元或胶质细胞)。我们 我将使用VA队列和现有的MRI数据来研究这些差异对神经完整性的影响 (N&gt；400)。通过这种方式，我们将把血液中与创伤后应激障碍相关的DNA甲基化差异与DNA甲基化联系起来 大脑的差异，大脑的基因表达差异，以及大脑的形态差异。 这将为创伤后应激障碍、创伤暴露和创伤后应激障碍相关症状提供临床上相关的生物标志物。 以及关于支持观察到的联系的生物学的重要信息。

Posttraumatic stress disorder (PTSD) is a serious mental disorder that occurs in response to a traumatic event. In this project, we will examine DNA methylation, an epigenetic form of gene regulation, for association with PTSD. We will utilize data from state of the art methylation beadchips that measure more than 850,000 locations along the genome. First, we will perform an epigenome-wide association study (EWAS) of PTSD in blood. This will be followed by a candidate gene analysis of PTSD and glucocorticoid-responsive genes based on our recent genome-wide gene expression study of PTSD (Logue et al., 2015). That study found genes whose expression in blood was closely correlated with PTSD case/control status, including many glucocorticoid-responsive genes that have not been previously studied in relationship to PTSD. These analyses will utilize data from two U.S. Department of Veterans Affairs (VA) cohorts (total n>1000) made up primarily of US veterans with a high prevalence of PTSD. Replication of these findings will be sought from a large epigenetics consortium. Then, we will perform genome-wide and candidate-gene association studies of PTSD using tissue from 50 brains obtained from a recently formed PTSD brain bank. We will specifically analyze methylation in the hippocampus, amygdala, and hypothalamus—three regions implicated in PTSD, HPA axis functioning, and anxiety. The impact of PTSD-associated differential methylation on gene expression in the brain will be investigated using chromogenic in-situ hybridization that will provide a measure of gene expression as well as provide localization of that expression to particular cell types (e.g. neurons or glia). We will investigate the effects of these differences on neural integrity using a VA cohort with existing MRI data (n>400). In this way, we will link PTSD-associated DNA methylation differences in blood to DNA methylation differences in the brain, gene-expression differences in the brain, and morphological differences in the brain. This will yield clinically relevant biomarkers for PTSD, trauma exposure, and PTSD-related symptomatology and important information about the biology underpinning the observed associations.