Katrinli Seyma, Wani Agaz H, Maihofer Adam X, Ratanatharathorn Andrew, Daskalakis Nikolaos P, Montalvo-Ortiz Janitza, Núñez-Ríos Diana L, Zannas Anthony S, Zhao Xiang, Aiello Allison E, Ashley-Koch Allison E, Avetyan Diana, Baker Dewleen G, Beckham Jean C, Boks Marco P, Brick Leslie A, Bromet Evelyn, Champagne Frances A, Chen Chia-Yen, Dalvie Shareefa, Dennis Michelle F, Fatumo Segun, Fortier Catherine, Galea Sandro, Garrett Melanie E, Geuze Elbert, Grant Gerald, Hayes Jasmeet P, Hemmings Sian Mj, Huber Bertrand Russel, Jajoo Aarti, Jansen Stefan, Kessler Ronald C, Kimbrel Nathan A, King Anthony P, Kleinman Joel E, Koen Nastassja, Koenen Karestan C, Kuan Pei-Fen, Liberzon Israel, Linnstaedt Sarah D, Lori Adriana, Luft Benjamin J, Luykx Jurjen J, Marx Christine E, McLean Samuel A, Mehta Divya, Milberg William, Miller Mark W, Mufford Mary S, Musanabaganwa Clarisse, Mutabaruka Jean, Mutesa Leon, Nemeroff Charles B, Nugent Nicole R, Orcutt Holly K, Qin Xue-Jun, Rauch Sheila A M, Ressler Kerry J, Risbrough Victoria B, Rutembesa Eugène, Rutten Bart P F, Seedat Soraya, Stein Dan J, Stein Murray B, Toikumo Sylvanus, Ursano Robert J, Uwineza Annette, Verfaellie Mieke H, Vermetten Eric, Vinkers Christiaan H, Ware Erin B, Wildman Derek E, Wolf Erika J, Young Ross McD, Zhao Ying, van den Heuvel Leigh L, Uddin Monica, Nievergelt Caroline M, Smith Alicia K, Logue Mark W
Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, US.
University of South Florida, Genomics Program, College of Public Health, Tampa, FL, US.
medRxiv. 2024 Jul 15:2024.07.15.24310422. doi: 10.1101/2024.07.15.24310422.
The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions.
As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress.
We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in and . Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels.
This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.
创伤事件后创伤后应激障碍（PTSD）的发生与生物学差异有关，这些差异可代表对PTSD的易感性、创伤的影响或PTSD本身的后遗症。这些影响包括DNA甲基化（DNAm）的差异，这是表观遗传基因调控的一种重要形式，存在于基因组多个CpG位点。此外，这些影响在中枢和外周组织中可能是共同的或特定的。在这里，我们旨在识别与PTSD相关的血液DNAm差异，并通过检查它们反映多个脑区关联的程度来表征潜在的生物学机制。
作为精神基因组学联盟（PGC）PTSD表观遗传学工作组，我们进行了迄今为止最大规模的PTSD全表观基因组关联研究（EWAS）横断面荟萃分析，涉及来自23项 civilian和军事研究的5077名参与者（2156例PTSD病例和2921名暴露于创伤的对照）。PTSD诊断评估按照PGC-PTSD工作组制定的标准化指南进行统一。使用Illumina HumanMethylation450或MethylationEPIC（850K）BeadChips从血液中检测DNAm。应用了通用的质量控制流程。在每个队列中，将DNA甲基化与PTSD、性别（如适用）、年龄、血细胞比例和祖先进行回归分析。进行了逆方差加权荟萃分析。我们在来自多个脑区、神经元细胞核的组织以及长期应激的细胞模型中进行了重复分析。
在总体荟萃分析中，我们确定了11个与PTSD相关的CpG位点（1.44e-09 < < 5.30e-08），以及在特定分层分析（军事与 civilian队列、性别和祖先）中确定的14个相关位点，包括 和 中的CpG。这些位点中的许多在甲基化水平上表现出血脑相关性，并在多个脑区与PTSD存在跨组织关联。大多数CpG的甲基化与其注释的基因表达水平相关。
本研究确定了11个与PTSD相关的CpG，还利用来自死后脑样本、全基因组关联研究（GWAS）和全基因组表达数据来解释这些关联背后的生物学机制，并对PTSD患者中调控不同的基因进行优先级排序。
