Methylome profile of World Trade Center related PTSD

世界贸易中心相关 PTSD 的甲基化概况

• 批准号: 10748071
• 负责人: Pei-Fen Kuan
• 金额: $ 49.96万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748071
• 关键词: Methylome; profile; World; Trade; Center

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.

抽象的 9/11世界贸易中心恐怖袭击是一场巨大的灾难，导致了长期的心理创伤 对于响应者，有17％的响应者经历了与PT​​SD一致的症状超过二十年 之后。 DNA甲基化，最广泛研究的表观遗传标记可以照亮基因 - 环境相互作用 并提供对PTSD病因和维持的生物学见解。虽然许多表观基因组 - 已经进行了广泛的关联研究（EWAS）来识别与PTSD相关的CPG，其中许多 研究的能力不足。持续解决单个队列的小样本量的努力包括 建立精神病基因组学联盟（PGC）PTSD表观遗传学工作组，这是最大的 迄今为止的表观遗传联盟。外周血中的大量样本母羊是可行的，并且有潜力 确定PTSD的可访问生物标志物，但是这些研究还强调了需要更多数据和更强大的生物标志物 设计。具体而言，PGC的局限性包括参与研究的大量方法论性异质性 同伙。拟议的研究通过使用更强大的设计来建立在现有研究的基础上，该设计将产生新颖 调查结果，同时允许将新数据与PGC数据相结合，以进一步增加功率和 确保结果的普遍性。为此，全基因组的甲基化分析与光明无源 将使用n = 1,850的一部分生物群样品生成甲基化的珠芯片阵列 被基因分型的响应者。在AIM 1中，将执行EWAS以识别与PTSD相关的CPG 和PTSD维度。在AIM 2中，将通过甲基化得出与甲基化相关的遗传变异 定量性状基因座分析并与PTSD遗传风险变异集成，以识别预期的因果CPG 和PTSD的变体。在AIM 3中，拟议研究的结果将与PGC结果结合在一起 最大化能力以检测可概括的发现。为了增强这项研究的影响，探索性目的是 包括以识别与PTSD和健康结果相关的甲基化亚类。这将是最大的 单核PTSD研究，并有助于识别新型的表观遗传机制，这些机制保持症状 慢性PTSD。这项研究将有助于在分子水平上阐明这种疾病的病理生理学，这 可能成为治疗开发的目标。