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Published VersionCC BY V4.0, Open Access
Journal article
Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: a meta-analysis of 23 military and civilian cohorts
Genome Medicine, Vol.16(1), pp.1-17
2024
PMID: 39696436
Abstract
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 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.
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.
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.
Details
- Title
- Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: a meta-analysis of 23 military and civilian cohorts
- Authors
- Seyma Katrinli - Emory UniversityAgaz H Wani - University of South FloridaAdam X Maihofer - University of California San DiegoAndrew Ratanatharathorn - Columbia UniversityNikolaos P Daskalakis - Harvard Medical SchoolJanitza Montalvo-Ortiz - National Center for Post Traumatic Stress DisorderDiana L Núñez-Ríos - VA Connecticut Healthcare SystemAnthony S Zannas - University of North Carolina at Chapel HillXiang Zhao - Boston UniversityAllison E Aiello - Columbia UniversityAllison E Ashley-Koch - Duke UniversityDiana Avetyan - University of California San DiegoDewleen G Baker - University of California San DiegoJean C Beckham - Duke UniversityMarco P Boks - University Medical Center UtrechtLeslie A Brick - Brown UniversityEvelyn Bromet - Stony Brook UniversityFrances A Champagne - The University of Texas at AustinChia-Yen Chen - Biogen (United States)Michelle F Dennis - Duke UniversityShareefa Dalvie - University of Cape TownSegun Fatumo - Uganda Virus Research InstituteCatherine Fortier - Harvard UniversitySandro Galea - Boston UniversityMelanie E Garrett - Duke UniversityElbert Geuze - Netherlands Federation of University Medical CentresGerald Grant - Duke UniversityMichael A Hauser - Duke UniversityJasmeet P Hayes - The Ohio State UniversitySian M J Hemmings - Stellenbosch UniversityBertrand Russel Huber - VA Boston Healthcare SystemAarti Jajoo - Broad InstituteStefan Jansen - University of RwandaRonald C Kessler - Harvard Medical SchoolNathan A Kimbrel - Duke UniversityAnthony P King - The Ohio State UniversityJoel E Kleinman - Johns Hopkins MedicineNastassja Koen - University of Cape TownKarestan C Koenen - Broad InstitutePei-Fen Kuan - Stony Brook UniversityIsrael Liberzon - Texas A&M UniversitySarah D Linnstaedt - University of North Carolina at Chapel HillAdriana Lori - Emory UniversityBenjamin J Luft - Stony Brook UniversityJurjen J Luykx - Amsterdam University Medical CentersChristine E Marx - Duke University School of MedicineSamuel A McLean - University of North Carolina Health CareDivya Mehta - Queensland University of TechnologyWilliam Milberg - VA Boston Healthcare SystemMark W Miller - National Center for Post Traumatic Stress DisorderMary S Mufford - University of Cape TownClarisse Musanabaganwa - Rwanda Biomedical CenterJean Mutabaruka - University of RwandaLeon Mutesa - University of RwandaCharles B Nemeroff - The University of Texas at AustinNicole R Nugent - Brown UniversityHolly K Orcutt - Northern Illinois UniversityXue-Jun Qin - Duke Molecular Physiology Institute, Duke University, Durham, NC, USASheila A M Rauch - Emory UniversityKerry J Ressler - Harvard Medical SchoolVictoria B Risbrough - University of California San Diego Medical CenterEugène Rutembesa - University of RwandaBart P F Rutten - Maastricht University Medical CentreSoraya Seedat - Stellenbosch UniversityDan J Stein - University of Cape TownMurray B Stein - University of California San DiegoSylvanus Toikumo - Western Cape Department of HealthRobert J Ursano - Uniformed Services University of the Health SciencesAnnette Uwineza - University of RwandaMieke H Verfaellie - Boston University School of MedicineEric Vermetten - New York UniversityChristiaan H Vinkers - Vrije Universiteit AmsterdamErin B Ware - University of MichiganDerek E Wildman - University of South FloridaErika J Wolf - VA Boston Healthcare SystemRoss Young - University of the Sunshine Coast, Queensland, Office of the Deputy Vice-Chancellor (Research and Innovation)Ying Zhao - University of North Carolina at Chapel HillLeigh L van den Heuvel - Stellenbosch UniversityPGC-PTSD Epigenetics Workgroup (Research Group)PsychENCODE PTSD Brainomics Project (Research Group)Traumatic Stress Brain Research Group (Research Group)Monica Uddin - University of FloridaCaroline M Nievergelt - University of California San DiegoAlicia K Smith - Emory UniversityMark W Logue - VA Boston Healthcare System
- Publication details
- Genome Medicine, Vol.16(1), pp.1-17
- Publisher
- BioMed Central Ltd.
- Date published
- 2024
- DOI
- 10.1186/s13073-024-01417-1
- ISSN
- 1756-994X
- PMID
- 39696436
- Copyright note
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Data Availability
- The main summary statistics data that support the findings of this study will be available within Supplementary Data upon publication. Individual-level data from the cohorts or cohort-level summary statistics will be made available to researchers following an approved analysis proposal through the PGC-PTSD Epigenetics Workgroup with the agreement of the cohort PIs. The raw data for the GTP cohort is available in the Gene Expression Omnibus database with the accession code GSE132203 [115]. Owing to limitations on data sharing as specified in the consent process and/or restrictions as part of the use agreement under which the data was accessed, data from the military/VA cohorts, VA MIRECC, MRS, Army STARRS, PRISMO, PROGrESS, and NCPTSD/TRACTS, cannot be publicly posted as part of this project. However, such data can be provided in de-identified form through a data use agreement following applicable guidelines on data sharing and privacy protection. For additional information on access to these data, including PI contact information for the cohorts accessed under a DUA, please contact the corresponding author.
- Grant note
- This work was supported by the National Institute of Mental Health (NIMH; R01MH108826 and R01MH106595). This work was also supported by I01BX003477, a Department of Veterans Affairs BLR&D grant to MWL; 1R03AG051877, 1R21AG061367-01, RF1AG068121, and 1I01CX001276-01A2 to EJW; R21MH102834, 5I01CX000431, 5R01MH079806 to MWM; R01MD011728 to MU; R01MH105379 to NRN; R01MH117291, R01MH117292, R01MH117293 to FAC; R01MH108826 to NPD; U01MH115485 to LM, SF, SJ, JM, AU, and DEW; R01MH117291, R01MH117292, R01MH117293 to JEK; CDC/NIOSH U01OH012466 to PFK; R01MH117291, R01MH117292, R01MH117293 to CBN; R01MH093500 to CMN; 1R15MH099521-01, 5R21MH085436-02, 1R15HD049907-01A1 to HKO; R01MH108826 to AKS; I01BX002577, IK2CX000525, and lK6BX003777 to NAK; U01MH110925 to SAM; R21DA050160 and 1DP1DA058737 to JMO; Department of Veterans Affairs B9254‐C to WM, B3001-C to CF; Department of Defense W81XWH-11–1-0073 and the National Center for Advancing Translational Sciences of the NIH UL1TR000433PEC-PTSD to SAMR; BX006186; BX005872 to VBR; VIDI award (91718336) from the Netherlands Scientific Organization to BPFR; Dutch Research Council (NWO) VIDI grant (09150171910042) to CHV. Brainomics work was supported by R01MH117291, R01MH117292, and R01MH117293. DJS and NK were supported by the South African Medical Research Council and the Bill and Melinda Gates Foundation (OPP 1017641). SS is supported by the South African Medical Research Council. SK is supported by the Building Interdisciplinary Research Careers in Women’s Health of the National Institutes of Health under Award Number K12HD085850.
- Organisation Unit
- Office of the Deputy Vice-Chancellor (Research and Innovation)
- Language
- English
- Record Identifier
- 991095345302621
- Output Type
- Journal article
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