Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: a meta-analysis of 23 military and civilian cohorts.
Journal: Genome medicine
Volume: 16
Issue: 1
Year of Publication: 2024
Affiliated Institutions:
Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA.
Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA.
Department of Psychiatry, University of California San Diego, La Jolla, CA, San Diego, USA.
Department of Epidemiology, Columbia University Mailmain School of Public Health, New York, NY, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
U.S. Department of Veterans Affairs National Center of Posttraumatic Stress Disorder, Clinical Neurosciences Division, West Haven, CT, USA.
Carolina Stress Initiative, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Robert N. Butler Columbia Aging Center, Department of Epidemiology, Columbia University, New York, NY, USA.
Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA.
Department of Psychiatry, Brain Center University Medical Center Utrecht, Utrecht, UT, NL, Netherlands.
Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
Epidemiology Research Group, State University of New York at Stony Brook, Stony Brook, NY, USA.
Department of Psychology, The University of Texas at Austin, Austin, TX, USA.
Biogen Inc, Translational Sciences, Cambridge, MA, USA.
Department of Pathology, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
MRC/UVRI and London School of Hygiene and Tropical Medicine, The African Computational Genomics (TACG) Research Group, Entebbe, Wakiso, Uganda.
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
School of Public Health, Boston University, Boston, MA, USA.
Brain Research and Innovation Centre, Netherlands Ministry of Defence, Utrecht, UT, NL, Netherlands.
Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Department of Psychology, The Ohio State University, Columbus, OH, USA.
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Western Cape, Cape Town, ZA, South Africa.
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
College of Medicine and Health Sciences, University of Rwanda, Kigali, RW, Rwanda.
Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Psychiatry & Mental Health, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA.
Department of Psychiatry and Behavioral Sciences, Texas A&M University College of Medicine, Bryan, TX, USA.
Department of Anesthesiology, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
Amsterdam Neuroscience Research Institute Stress & Sleep Program, Amsterdam University Medical Center, Amsterdam, NH, Netherlands.
Department of Psychiatry, UNC Institute for Trauma Recovery, NC, Chapel Hill, USA.
Centre for Genomics and Personalised Health, Queensland University of Technology, Kelvin Grove, QLD, AU, Brisbane, Australia.
GRECC/TRACTS, VA Boston Healthcare System, Boston, MA, USA.
Biomedical Genetics & Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Department of Psychiatry and Mental Health, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
Research Innovation and Data Science Division, Rwanda Biomedical Center, Kigali, Rwanda.
Department of Clinical Psychology, University of Rwanda, Huye, RW, Rwanda.
Department of Emergency Medicine, Alpert Brown Medical School, Providence, RI, USA.
Department of Psychology, Northern Illinois University, DeKalb, IL, USA.
Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA, USA.
Clinical Psychology, University of Rwanda, Kigali, RW, Rwanda.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht Universitair Medisch Centrum, Maastricht, Limburg, NL, Netherlands.
Department of Psychiatry, Center for the Study of Traumatic Stress, Uniformed Services University, Bethesda, MD, USA.
College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda.
Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
Department of Psychiatry, Leiden University Medical Center, Leiden, ZH, NL, Netherlands.
Department of Anatomy and Neurosciences, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Holland, Netherlands.
Survey Research Center, University of Michigan, Ann Arbor, MI, USA.
College of Public Health, University of South Florida, Tampa, FL, USA.
National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.
School of Clinical Sciences, Queensland University of Technology, Kelvin Grove, QLD, AU, Brisbane, Australia.
Institute for Trauma Recovery, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
University of South Florida College of Public Health, Genomics Program, Tampa, FL, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. loguem@bu.edu.
Abstract summary
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.
Authors & Co-authors:
Katrinli Seyma S
Wani Agaz H AH
Maihofer Adam X AX
Ratanatharathorn Andrew A
Daskalakis Nikolaos P NP
Montalvo-Ortiz Janitza J
Núñez-Ríos Diana L DL
Zannas Anthony S AS
Zhao Xiang X
Aiello Allison E AE
Ashley-Koch Allison E AE
Avetyan Diana D
Baker Dewleen G DG
Beckham Jean C JC
Boks Marco P MP
Brick Leslie A LA
Bromet Evelyn E
Champagne Frances A FA
Chen Chia-Yen CY
Dalvie Shareefa S
Dennis Michelle F MF
Fatumo Segun S
Fortier Catherine C
Galea Sandro S
Garrett Melanie E ME
Geuze Elbert E
Grant Gerald G
Hauser Michael A MA
Hayes Jasmeet P JP
Hemmings Sian M J SMJ
Huber Bertrand Russel BR
Jajoo Aarti A
Jansen Stefan S
Kessler Ronald C RC
Kimbrel Nathan A NA
King Anthony P AP
Kleinman Joel E JE
Koen Nastassja N
Koenen Karestan C KC
Kuan Pei-Fen PF
Liberzon Israel I
Linnstaedt Sarah D SD
Lori Adriana A
Luft Benjamin J BJ
Luykx Jurjen J JJ
Marx Christine E CE
McLean Samuel A SA
Mehta Divya D
Milberg William W
Miller Mark W MW
Mufford Mary S MS
Musanabaganwa Clarisse C
Mutabaruka Jean J
Mutesa Leon L
Nemeroff Charles B CB
Nugent Nicole R NR
Orcutt Holly K HK
Qin Xue-Jun XJ
Rauch Sheila A M SAM
Ressler Kerry J KJ
Risbrough Victoria B VB
Rutembesa Eugène E
Rutten Bart P F BPF
Seedat Soraya S
Stein Dan J DJ
Stein Murray B MB
Toikumo Sylvanus S
Ursano Robert J RJ
Uwineza Annette A
Verfaellie Mieke H MH
Vermetten Eric E
Vinkers Christiaan H CH
Ware Erin B EB
Wildman Derek E DE
Wolf Erika J EJ
Young Ross McD RM
Zhao Ying Y
van den Heuvel Leigh L LL
Uddin Monica M
Nievergelt Caroline M CM
Smith Alicia K AK
Logue Mark W MW
Study Outcome
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