Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts.

Journal: medRxiv : the preprint server for health sciences

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Affiliated Institutions:  Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, US. University of South Florida, Genomics Program, College of Public Health, Tampa, FL, US. University of California San Diego, Department of Psychiatry, La Jolla, CA, US. Columbia University Mailmain School of Public Health, Department of Epidemiology, New York, NY, US. Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, US. U.S. Department of Veterans Affairs National Center of Posttraumatic Stress Disorder, Clinical Neurosciences Division, West Haven, CT, US. University of North Carolina at Chapel Hill, Carolina Stress Initiative, Chapel Hill, NC, US. Boston University School of Public Health, Department of Biostatistics, Boston, MA, US. Columbia University, Robert N Butler Columbia Aging Center, Department of Epidemiology, New York, NY, US. Duke University Medical Center, Duke Molecular Physiology Institute, Durham, NC, US. Duke University School of Medicine, Department of Psychiatry and Behavioral Sciences, Durham, NC, US. Brain Center University Medical Center Utrecht, Department of Psychiatry, Utrecht, UT, NL. Alpert Medical School of Brown University, Department of Psychiatry and Human Behavior, Providence, RI, US. State University of New York at Stony Brook, Epidemiology Research Group, Stony Brook, NY, US. The University of Texas at Austin, Department of Psychology, Austin, TX, US. Biogen Inc., Translational Sciences, Cambridge, MA, US. University of Cape Town, Department of Pathology, Cape Town, Western Province, ZA. MRC/UVRI and London School of Hygiene and Tropical Medicine, The African Computational Genomics (TACG) Research Group, Entebbe, Wakiso, Uganda. Harvard Medical School, Department of Psychiatry, Boston, MA, US. Boston University School of Public Health, Boston, MA, US. Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, UT, NL. Duke University School of Medicine, Department of Neurosurgery, Durham, NC, US. Duke University School of Medicine, Department of Medicine, Durham, NC, US. The Ohio State University, Department of Psychology, Columbus, OH, US. Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Psychiatry, Cape Town, Western Cape, ZA. Boston University School of Medicine, Department of Neurology, Boston, MA, US. University of Rwanda, College of Medicine and Health Sciences, Kigali, RW. Harvard Medical School, Department of Health Care Policy, Boston, MA, US. The Ohio State University, College of Medicine, Institute for Behavioral Medicine Research, Columbus, OH, US. Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Baltimore, MD, US. University of Cape Town, Department of Psychiatry & Mental Health, Cape Town, Western Province, ZA. Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA, US. Stony Brook University, Department of Applied Mathematics and Statistics, Stony Brook, NY, US. Texas A&M University College of Medicine, Department of Psychiatry and Behavioral Sciences, Bryan, TX, US. University of North Carolina at Chapel Hill, Department of Anesthesiology, Chapel Hill, NC, US. Emory University, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, US. Stony Brook University, Department of Medicine, Stony Brook, NY, US. Amsterdam University Medical Center, Amsterdam Neuroscience Research Institute, Mood, Anxiety, Psychosis, Stress & Sleep Program, Amsterdam, NH, NL. UNC Institute for Trauma Recovery, Department of Psychiatry, Chapel Hill, NC, US. Queensland University of Technology, Centre for Genomics and Personalised Health, Kelvin Grove, QLD, AU. VA Boston Healthcare System, GRECC/TRACTS, Boston, MA, US. Boston University School of Medicine, Psychiatry, Biomedical Genetics, Boston, MA, US. University of Cape Town, Department of Psychiatry and Mental Health, Cape Town, Western Province, ZA. Rwanda Biomedical Center, Research Innovation and Data Science Division, Kigali, RW. University of Rwanda, Department of Clinical Psychology, Huye, RW. Alpert Brown Medical School, Department of Emergency Medicine, Providence, RI, US. Northern Illinois University, Department of Psychology, DeKalb, IL, US. Duke University, Duke Molecular Physiology Institute, Durham, NC, US. Emory University, Department of Psychiatry & Behavioral Sciences, Atlanta, GA, US. University of Rwanda, Clinical Psychology, Kigali, RW, Rwanda. Maastricht Universitair Medisch Centrum, School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht, Limburg, NL. Uniformed Services University, Center for the Study of Traumatic Stress, Department of Psychiatry, Bethesda, Maryland, US. University of Rwanda, College of Medicine and Health Sciences, Kigali, Rwanda. Boston University School of Medicine, Department of Psychiatry, Boston, MA, US. Leiden University Medical Center, Department of Psychiatry, Leiden, ZH, NL. Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Amsterdam, Holland, NL. University of Michigan, Survey Research Center, Ann Arbor, MI, US. University of South Florida, College of Public Health, Tampa, FL, US. VA Boston Healthcare System, National Center for PTSD, Boston, MA, US. Queensland University of Technology, School of Clinical Sciences, Kelvin Grove, QLD, AU. University of North Carolina at Chapel Hill, Institute for Trauma Recovery, Chapel Hill, NC, US. University of South Florida College of Public Health, Genomics Program, Tampa, FL, US.

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 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.

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 Michael A Hauser Hayes Jasmeet P JP Hemmings Sian Mj SM 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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Statistics
Citations :  American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 2013.
Authors :  83
Identifiers
Doi : 2024.07.15.24310422
SSN : 
Study Population
Male,Female
Mesh Terms
Other Terms
DNA methylation;GWAS;PTSD;gene expression;postmortem brain;trauma
Study Design
Cross Sectional Study
Study Approach
Country of Study
Publication Country
United States