Genetic and Epigenetic Biomarkers of PTSD

创伤后应激障碍（PTSD）是一种严重的精神障碍， 创伤性事件在这个项目中，我们将研究DNA甲基化，一种基因调控的表观遗传形式， 与PTSD有关。我们将利用来自最先进的甲基化珠芯片的数据， 基因组上有85万个沿着的位置。首先，我们将进行表观全基因组关联研究（EWAS）， 血液中的PTSD随后将进行PTSD和糖皮质激素敏感性的候选基因分析。 基于我们最近的PTSD的全基因组基因表达研究（Logue等，2015）。该研究 发现血液中的表达与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PTSD的关系。这些 分析将利用来自美国退伍军人事务部（VA）两个队列（总数n>1000）的数据， 主要是创伤后应激障碍高发的美国退伍军人。这些发现的复制将从一个 大型表观遗传学财团然后，我们将进行全基因组和候选基因关联研究， PTSD使用的是从最近成立的PTSD脑库中获得的50个大脑组织。我们将特别 分析海马、杏仁核和下丘脑的甲基化--这三个区域与创伤后应激障碍有关， 下丘脑-垂体-肾上腺轴功能和焦虑。PTSD相关的差异甲基化对基因表达的影响 将使用显色原位杂交来研究大脑中的基因， 表达以及将该表达定位于特定细胞类型（例如神经元或神经胶质）。我们 将使用具有现有MRI数据的VA队列研究这些差异对神经完整性的影响 （n>400）。通过这种方式，我们将血液中PTSD相关的DNA甲基化差异与DNA甲基化联系起来 大脑中的差异，大脑中的基因表达差异，以及大脑中的形态差异。 这将产生临床相关的生物标志物创伤后应激障碍，创伤暴露，创伤后应激障碍相关的病理学 以及关于支撑观察到的关联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.