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

项目摘要 目前尚不清楚为什么有些人会在创伤事件后发展为创伤后应激障碍（PTSD）。 DNA甲基化是一种与创伤和其他环境暴露有关的表观遗传标记， 在多项研究中，PTSD与DNA甲基化有关，一些基因的DNA甲基化可能为PTSD的早期诊断提供信息。 PTSD的预测和治疗。在过去的3年里，精神病学的表观遗传学工作组 PTSD基因组学联盟（PGC-PTSD）汇集了来自10项研究的数据， 来自10个国家的研究人员，以促进交叉DNA甲基化（DNAm）数据的荟萃分析， 在平民和军人队列中进行PTSD的纵向和横向研究。在这份更新提案中，我们将 通过在一项独立的荟萃分析中复制我们的发现， 迄今为止，在超过4，700名受试者中进行了最大规模的表观基因组关联研究（EWAS）， PTSD相关的CpG在死后脑组织，确定甲基化数量性状基因座（meQTL）， 与PTSD相关的血液和脑，并表征PTSD治疗过程中的DNAm变化。我们 准备快速有效地鉴定为早期预测和治疗提供信息的表观遗传标记 并提供遗传变异的背景，以预测创伤事件后的风险和恢复力。这项研究， 这与正在进行的PGC-PTSD的努力相一致，将告知该领域的关键问题， 基于血液的甲基化模式作为临床信息生物标志物，以及它们反映 大脑中的后生模式;它还将提供对创伤后应激障碍的生物学途径的深入了解， 补充正在进行的确定治疗靶点的努力，并为PTSD和创伤的前瞻性研究提供信息。 正在进行的曝光。

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.