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，是由于对创伤后应激障碍的反应而发生的。 在这个项目中，我们将检查 DNA 甲基化，这是基因调控的一种表观遗传形式。 我们将利用最先进的甲基化珠芯片的数据来测量超过 首先，我们将对基因组上的 850,000 个位置进行全表观基因组关联研究 (EWAS)。 随后将进行 PTSD 和糖皮质激素反应的候选基因分析。 基于我们最近的 PTSD 全基因组基因表达研究（Logue 等人，2015）。 发现血液中表达与 PTSD 病例/对照状态密切相关的基因，包括许多 先前尚未研究过与 PTSD 关系的糖皮质激素反应基因。 分析将利用来自美国退伍军人事务部 (VA) 的两个队列（总数 n>1000）的数据 主要针对患有创伤后应激障碍 (PTSD) 患病率较高的美国退伍军人，将寻求重复这些发现。 然后，我们将进行全基因组和候选基因关联研究。 PTSD 使用从最近成立的 PTSD 脑库中获得的 50 个大脑组织。 分析海马体、杏仁核和下丘脑的甲基化——与 PTSD 相关的三个区域， HPA 轴功能和焦虑与 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，这将提供基因的测量 表达以及将该表达定位到特定细胞类型（例如神经元或神经胶质细胞）。 将使用 VA 队列和现有 MRI 数据来研究这些差异对神经完整性的影响 (n>400)，我们将血液中与 PTSD 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。 这将产生 PTSD、创伤暴露和 PTSD 相关症状的临床相关生物标志物 以及有关支持观察到的关联的生物学的重要信息。