Genetic and Epigenetic Biomarkers of PTSD

PTSD 的遗传和表观遗传生物标志物

• 批准号: 9241069
• 负责人: MARK W LOGUE
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241069
• 关键词: Amygdaloid structure; Anxiety; Biological; Biological Markers; Biology; Blood; Blood Cells; Blood specimen; Brain; Brain Diseases; Candidate Disease Gene; Caring; Cells; Chromogenic in situ Hybridization; CpG dinucleotide; DNA; DNA Methylation; Data; Development; Disease; Ensure; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Family; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Markers; Genetic Variation; Genome; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; High Prevalence; Hippocampus (Brain); Hypothalamic structure; In Situ Hybridization; Lead; Life; Link; Literature; Location; Magnetic Resonance Imaging; Measures; Mediating; Methylation; NR3C1 gene; Neurobiology; Neuroglia; Neurons; Patients; Pattern; Post-Traumatic Stress Disorders; Prevalence; Psychoneuroendocrinology; Psychopathology; Receptor Gene; Reporting; Sampling; Signal Transduction; Site; Societies; Structure; Testing; Thick; Tissues; Trauma; Veterans; base; bead chip; brain morphology; brain tissue; brain volume; case control; cell type; clinically relevant; cohort; combat; differential expression; disorder risk; epigenetic marker; epigenome-wide association studies; experimental study; genetic profiling; genome wide methylation; genome-wide; genome-wide analysis; individual patient; methyl group; methylation biomarker; methylation pattern; mind control; novel marker; potential biomarker; relating to nervous system; response; severe mental illness; symptomatology; traumatic event

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.

创伤后应激障碍（PTSD）是一种严重的精神障碍 创伤事件。在这个项目中，我们将研究DNA甲基化，这是一种基因调节的表观遗传形式，用于 与PTSD的关联。我们将利用来自最先进的甲基化珠芯片的数据，这些数据测量超过 基因组沿线850,000个位置。首先，我们将进行全基因组的关联研究（EWAS） 血液中的PTSD。随后将进行PTSD和糖皮质激素响应的候选基因分析 基于我们最近全基因组基因表达研究的基因研究（Logue等，2015）。那个研究 发现其在血液中表达与PTSD病例/控制状态紧密相关的基因，包括许多 糖皮质激素反应性基因以前尚未与PTSD相关。这些 分析将利用美国两个退伍军人事务部（VA）同伙（总计n> 1000）的数据 首先，我们的退伍军人患有PTSD的流行率很高。这些发现的复制将从一个 大型表观遗传学财团。然后，我们将对全基因组和候选基因关联研究 PTSD使用来自最近形成的PTSD脑库的50个大脑的组织。我们将具体 分析海马，杏仁核和下丘脑中的甲基化 - 在PTSD中实施的三个区域 HPA轴功能和焦虑。 PTSD相关的差甲基化对基因表达的影响 在大脑中，将使用成色的原位杂交研究，该杂交将提供基因的量度 表达并提供该表达的定位到特定细胞类型（例如神经元或神经胶质）。我们 将使用现有MRI数据的VA队列研究这些差异对神经完整性的影响 （n> 400）。这样，我们将将血液中PTSD相关的DNA甲基化差异与DNA甲基化联系 大脑的差异，大脑的基因表达差异以及大脑的形态差异。 这将产生与PTSD，创伤暴露和PTSD相关症状学的临床相关生物标志物 以及有关生物学基础的重要信息。