Epigenome-Wide Association Studies Identify Novel DNA Methylation Sites Associated with PTSD: A Meta-Analysis of 23 Military and Civilian Cohorts

Details

• Personal Author:
  Aiello AE ; Ashley-Koch AE ; Avetyan D ; Baker DG ; Beckham JC ; Boks MP ; Brick LA ; Bromet E ; Champagne FA ; Chen C-Y ; Dalvie S ; Daskalakis NP ; Dennis MF ; Fatumo S ; Fortier C ; Galea S ; Garrett ME ; Geuze E ; Grant G ; Hauser MA ; Hayes JP ; Hemmings SMJ ; Huber BR ; Jajoo A ; Jansen S ; Katrinli S ; Kessler RC ; Kimbrel NA ; King AP ; Kleinman JE ; Koen N ; Koenen KC ; Kuan P-F ; Liberzon I ; Linnstaedt SD ; Lori A ; Luft BJ ; Luykx JJ ; Maihofer AX ; Marx CE ; McLean SA ; Mehta D ; Milberg W ; Miller MW ; Montalvo-Ortiz J ; Mufford MS ; Musanabaganwa C ; Mutabaruka J ; Mutesa L ; Nemeroff CB ; Nugent NR ; Núñez-Ríos DL ; Orcutt HK ; PGC-PTSD Epigenetics Workgroup ; PsychENCODE PTSD Brainomics Project ; Qin X-J ; Ratanatharathorn A ; Rauch SAM ; Ressler KJ ; Risbrough VB ; Rutembesa E ; Rutten BPF ; Seedat S ; Stein DJ ; Stein MB ; Toikumo S ; Traumatic Stress Brain Research Group ; Uddin M ; Ursano RJ ; Uwineza A ; van den Heuvel LL ; Verfaellie MH ; Vermetten E ; Vinkers CH ; Wani AH ; Ware EB ; Wildman DE ; Wolf EJ ; Young RM ; Zannas AS ; Zhao X ; Zhao Y
• Description:
  Background: 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. Methods: 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 Illumina HumanMethylation450 or MethylationEPIC (850 K) BeadChips. 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. Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e - 09 < p < 5.30e - 08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Out of 9 CpGs annotated to a gene expressed in blood, methylation levels at 5 CpGs showed significant correlations with the expression levels of their respective annotated genes. Conclusions: This study identifies 11 PTSD-associated CpGs and 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. [Description provided by NIOSH]
• Subjects:
  Epidemiology Genetics Occupational Health Safety Stress Disorders, Post-Traumatic
• Keywords:
  Author Keywords: PTSD Cross Sectional Studies DNA Damage DNA Methylation Gene Expression Genomics GWAS Post-traumatic Stress Disorder Postmortem Brain PTSD Trauma Traumatic Incident Stress

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• ISSN:
  1756-994X
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Atlanta Region [OSHA] ; Birmingham Region [OSHA] ; Boston Region [OSHA] ; California ; Chicago Region [OSHA] ; Connecticut ; Dallas Region [OSHA] ; Florida ; Georgia ; Illinois ; Maryland ; Massachusetts ; New York ; New York City Region [OSHA] ; North Carolina ; Ohio ; Philadelphia Region [OSHA] ; Rhode Island ; San Francisco Region [OSHA] ; Texas
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  16
• NIOSHTIC Number:
  nn:20070629
• Citation:
  Genome Med 2024 Dec; 16:147
• Contact Point Address:
  Mark W. Logue. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
• Email:
  loguem@bu.edu
• Federal Fiscal Year:
  2025
• Performing Organization:
  State University of New York Stony Brook
• Peer Reviewed:
  True
• Start Date:
  20230701
• Source Full Name:
  Genome Medicine
• End Date:
  20260630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:715014a7a654f8aa1f04b934369b3e97cfec79a0db8c009b29cdcd4f43d0a22a88cc66d30293a0e87f9eb1715dc72dc56e803bbd4ae1f0f74c2c373f4db3c59a
• Download URL:
  https://stacks.cdc.gov/view/cdc/208808/cdc_208808_DS1.pdf
• File Type:
  [PDF - 2.22 MB ]