The Impact of Traumatic Stress on the Methylome: implications for PTSD

创伤性应激对甲基组的影响：对 PTSD 的影响

• 批准号: 10414121
• 负责人: MARK W LOGUE
• 金额: $ 70.24万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-18 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414121
• 关键词: Age; Autopsy; Bioinformatics; Biological; Biological Markers; Blood; Brain; Brain region; Cells; Clinical; Collaborations; Complement; Country; Cross-Sectional Studies; DNA Methylation; DNA analysis; Data; Ensure; Environmental Exposure; Epigenetic Process; Exhibits; Exposure to; Freezing; Genes; Genetic; Genotype; Longitudinal Studies; Measures; Mendelian randomization; Meta-Analysis; Metadata; Methylation; Military Personnel; Neuroglia; Neurons; Paper; Pathway interactions; Patients; Pattern; Peripheral; Persons; Post-Traumatic Stress Disorders; Prospective Studies; Quantitative Trait Loci; Reporting; Reproducibility; Research Personnel; Risk; Role; Sampling; Severities; Signal Transduction; Site; Symptoms; Testing; Tissues; Trauma; Work; base; bisulfite; brain tissue; case control; cohort; epigenetic marker; epigenome-wide association studies; genetic variant; genome-wide; insight; methylation pattern; methylome; pediatric trauma; prospective; psychiatric genomics; resilience; responders and non-responders; response; stress related disorder; symptom treatment; therapeutic target; therapy development; trauma exposure; traumatic event; traumatic stress; treatment response; whole genome

Project Summary It is not clear why some people develop posttraumatic stress disorder (PTSD) in response to a traumatic event. DNA methylation, an epigenetic mark that associates with trauma and other environmental exposures, associates with PTSD in multiple studies, and DNA methylation of some genes may be informative for early prediction and treatment of PTSD. Over the last 3 years, the Epigenetics Workgroup of the Psychiatric Genomics Consortium for PTSD (PGC-PTSD) has brought together data from 10 studies, with over 90 investigators from 10 countries to facilitate meta-analyses of DNA methylation (DNAm) data from cross- sectional and longitudinal studies of PTSD in civilian and military cohorts. In this renewal proposal, we will build on this highly productive collaboration by replicating our findings in an independent meta-analysis and performing the largest epigenome-wide association study (EWAS) to date in >4,700 subjects, characterizing PTSD-associated CpGs in postmortem brain tissue, identifying methylation quantitative trait loci (meQTLs) in blood and brain relevant to PTSD, and characterizing DNAm changes over the course of PTSD treatment. We are poised to rapidly and efficiently identify epigenetic markers informative for early prediction and treatment and to provide context to genetic variants that predict risk and resilience following traumatic events. This study, which aligns with ongoing PGC-PTSD efforts, will inform critical questions in the field related to the role of blood-based methylation patterns as clinically-informative biomarkers and the degree to which they reflect epigentic patterns in the brain; it will also provide insight into the biologic pathways underlying PTSD, complement ongoing efforts to identify therapeutic targets, and inform prospective studies of PTSD and trauma exposure that are underway.

项目概要 目前尚不清楚为什么有些人因创伤事件而出现创伤后应激障碍（PTSD）。 DNA 甲基化是一种与创伤和其他环境暴露相关的表观遗传标记， 多项研究表明，DNA 与 PTSD 相关，某些基因的 DNA 甲基化可能为早期诊断提供信息。 PTSD 的预测和治疗。在过去 3 年里，精神科表观遗传学工作组 PTSD 基因组学联盟 (PGC-PTSD) 汇集了 10 项研究的数据，其中 90 多项 来自 10 个国家的研究人员促进对来自交叉研究的 DNA 甲基化 (DNAm) 数据进行荟萃分析 对平民和军人群体进行创伤后应激障碍 (PTSD) 的分段和纵向研究。在本次更新提案中，我们将 通过在独立的荟萃分析中复制我们的发现，建立在这种高效合作的基础上 对超过 4,700 名受试者进行迄今为止最大规模的全表观基因组关联研究 (EWAS)， 死后脑组织中与 PTSD 相关的 CpG，识别其中的甲基化数量性状位点 (meQTL) 与 PTSD 相关的血液和大脑，以及描述 PTSD 治疗过程中 DNAm 变化的特征。我们 准备快速有效地识别为早期预测和治疗提供信息的表观遗传标记 并为预测创伤事件后的风险和恢复力的遗传变异提供背景。这项研究， 与正在进行的 PGC-PTSD 工作相一致，将告知与以下角色相关的领域的关键问题： 作为临床信息生物标志物的血液甲基化模式及其反映的程度 大脑中的表观遗传模式；它还将提供对创伤后应激障碍（PTSD）潜在生物学途径的深入了解， 补充目前确定治疗目标的努力，并为 PTSD 和创伤的前瞻性研究提供信息 正在进行的曝光。