Methylome profile of World Trade Center related PTSD

摘要 9·11世贸中心恐怖袭击是一场巨大的灾难，造成了长期的心理创伤 对于应答者来说，17%的应答者经历了20多年来与创伤后应激障碍相一致的症状 后来。DNA甲基化，最广泛研究的表观遗传标记，可以阐明基因与环境的相互作用 并为创伤后应激障碍的病因和维持提供生物学见解。尽管有一些表观基因组- 已经进行了广泛的关联研究(Ewas)来确定与创伤后应激障碍相关的CPG，其中许多 研究的动力不足。正在进行的解决小样本个体队列问题的努力包括 建立最大的精神病基因组学联盟(PGC)创伤后应激障碍表观遗传学工作组 到目前为止表观遗传联盟。在外周血中进行大样本EIA是可行的，并有可能 确定可用于创伤后应激障碍的生物标志物，然而，这些研究也强调了需要更多的数据和更强有力的 设计。具体地说，PGC的局限性包括参与研究的方法学上的巨大异质性 一群人。拟议的研究建立在现有研究的基础上，通过使用更强大的设计来产生新奇的 调查结果，同时允许新数据与PGC数据相结合，以进一步增加权力和 确保结果的概括性。为此，利用Illumina Infinium进行全基因组甲基化分析 甲基EPIC珠片阵列将使用n=1,850个子集的生物库血液样本生成 已经进行了基因分型的应答者。在目标1中，将进行Ewas以确定与创伤后应激障碍相关的CPG 和创伤后应激障碍维度。在目标2中，与甲基化相关的遗传变异将通过甲基化得到 数量性状基因座分析并与创伤后应激障碍遗传风险变量相结合以识别推测的原因CPGS 以及创伤后应激障碍的变种。在目标3中，拟议研究的结果将与PGC的结果相结合，以 最大限度地提高检测可概括结论的能力。为了加强这项研究的影响，一个探索性的目的是 包括确定与创伤后应激障碍和健康结果相关的甲基化亚类。这将是世界上最大的 单队列创伤后应激障碍研究，旨在确定维持症状的新表观遗传机制 慢性创伤后应激障碍。这项研究将有助于从分子水平上阐明这种疾病的病理生理机制。 可能成为治疗发展的目标。

ABSTRACT The 9/11 World Trade Center terrorist attack was a massive disaster, resulting in long-term psychological trauma to the responders, with 17% of responders experiencing symptoms consistent with PTSD more than two decades later. DNA methylation, the most widely studied epigenetic mark can illuminate gene-environment interaction and provide biological insights into the etiology and maintenance of PTSD. Although a number of epigenome- wide association studies (EWAS) have been conducted to identify CpGs associated with PTSD, many of these studies are underpowered. Ongoing efforts to address small sample sizes of individual cohort include establishing the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, which is the largest epigenetic consortium to date. Large sample EWAS in peripheral blood are feasible and have the potential to identify accessible biomarker for PTSD, however these studies also highlight the need for more data and stronger designs. Specifically, the limitations of PGC include large methodological heterogeneity of the participating study cohorts. The proposed study builds on existing studies by using more powerful design that will produce novel findings, and at the same time allow new data to be combined with PGC data to further increase power and ensure generalizability of the results. To this end, genome-wide methylation profiling with the Illumina Infinium MethylationEPIC BeadChip arrays will be generated using biobanked blood samples on a subset of n=1,850 responders who have been genotyped. In Aim 1, EWAS will be performed to identify CpGs associated with PTSD and PTSD dimensions. In Aim 2, genetic variants associated with methylation will be derived via methylation quantitative trait loci analysis and integrated with PTSD genetic risk variants to identify putatively causal CpGs and variants for PTSD. In Aim 3, results from the proposed study will be combined with the PGC results to maximize power to detect generalizable findings. To enhance the impact of this study, an exploratory aim is included to identify methylation subclasses associated with PTSD and health outcomes. This will be the largest single-cohort PTSD study and is powered to identify novel epigenetic mechanisms that maintain symptoms in chronic PTSD. This research will help to explicate pathophysiology of this disorders on molecular level, which may become targets for treatment development.