Genome Medicine (Dec 2024)
Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: a meta-analysis of 23 military and civilian cohorts
- Seyma Katrinli,
- Agaz H. Wani,
- Adam X. Maihofer,
- Andrew Ratanatharathorn,
- Nikolaos P. Daskalakis,
- Janitza Montalvo-Ortiz,
- Diana L. Núñez-Ríos,
- Anthony S. Zannas,
- Xiang Zhao,
- Allison E. Aiello,
- Allison E. Ashley-Koch,
- Diana Avetyan,
- Dewleen G. Baker,
- Jean C. Beckham,
- Marco P. Boks,
- Leslie A. Brick,
- Evelyn Bromet,
- Frances A. Champagne,
- Chia-Yen Chen,
- Shareefa Dalvie,
- Michelle F. Dennis,
- Segun Fatumo,
- Catherine Fortier,
- Sandro Galea,
- Melanie E. Garrett,
- Elbert Geuze,
- Gerald Grant,
- Michael A. Hauser,
- Jasmeet P. Hayes,
- Sian M. J. Hemmings,
- Bertrand Russel Huber,
- Aarti Jajoo,
- Stefan Jansen,
- Ronald C. Kessler,
- Nathan A. Kimbrel,
- Anthony P. King,
- Joel E. Kleinman,
- Nastassja Koen,
- Karestan C. Koenen,
- Pei-Fen Kuan,
- Israel Liberzon,
- Sarah D. Linnstaedt,
- Adriana Lori,
- Benjamin J. Luft,
- Jurjen J. Luykx,
- Christine E. Marx,
- Samuel A. McLean,
- Divya Mehta,
- William Milberg,
- Mark W. Miller,
- Mary S. Mufford,
- Clarisse Musanabaganwa,
- Jean Mutabaruka,
- Leon Mutesa,
- Charles B. Nemeroff,
- Nicole R. Nugent,
- Holly K. Orcutt,
- Xue-Jun Qin,
- Sheila A. M. Rauch,
- Kerry J. Ressler,
- Victoria B. Risbrough,
- Eugène Rutembesa,
- Bart P. F. Rutten,
- Soraya Seedat,
- Dan J. Stein,
- Murray B. Stein,
- Sylvanus Toikumo,
- Robert J. Ursano,
- Annette Uwineza,
- Mieke H. Verfaellie,
- Eric Vermetten,
- Christiaan H. Vinkers,
- Erin B. Ware,
- Derek E. Wildman,
- Erika J. Wolf,
- Ross McD Young,
- Ying Zhao,
- Leigh L. van den Heuvel,
- PGC-PTSD Epigenetics Workgroup,
- PsychENCODE PTSD Brainomics Project,
- Traumatic Stress Brain Research Group,
- Monica Uddin,
- Caroline M. Nievergelt,
- Alicia K. Smith,
- Mark W. Logue
Affiliations
- Seyma Katrinli
- Department of Gynecology and Obstetrics, Emory University
- Agaz H. Wani
- Genomics Program, College of Public Health, University of South Florida
- Adam X. Maihofer
- Department of Psychiatry, University of California San Diego
- Andrew Ratanatharathorn
- Department of Epidemiology, Columbia University Mailmain School of Public Health
- Nikolaos P. Daskalakis
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
- Janitza Montalvo-Ortiz
- U.S. Department of Veterans Affairs National Center of Posttraumatic Stress Disorder, Clinical Neurosciences Division
- Diana L. Núñez-Ríos
- U.S. Department of Veterans Affairs National Center of Posttraumatic Stress Disorder, Clinical Neurosciences Division
- Anthony S. Zannas
- Carolina Stress Initiative, University of North Carolina at Chapel Hill
- Xiang Zhao
- Department of Biostatistics, Boston University School of Public Health
- Allison E. Aiello
- Robert N. Butler Columbia Aging Center, Department of Epidemiology, Columbia University
- Allison E. Ashley-Koch
- Duke Molecular Physiology Institute, Duke University Medical Center
- Diana Avetyan
- Department of Psychiatry, University of California San Diego
- Dewleen G. Baker
- Department of Psychiatry, University of California San Diego
- Jean C. Beckham
- Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine
- Marco P. Boks
- Department of Psychiatry, Brain Center University Medical Center Utrecht
- Leslie A. Brick
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University
- Evelyn Bromet
- Epidemiology Research Group, State University of New York at Stony Brook
- Frances A. Champagne
- Department of Psychology, The University of Texas at Austin
- Chia-Yen Chen
- Biogen Inc, Translational Sciences
- Shareefa Dalvie
- Department of Pathology, University of Cape Town
- Michelle F. Dennis
- Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine
- Segun Fatumo
- MRC/UVRI and London School of Hygiene and Tropical Medicine, The African Computational Genomics (TACG) Research Group
- Catherine Fortier
- Department of Psychiatry, Harvard Medical School
- Sandro Galea
- School of Public Health, Boston University
- Melanie E. Garrett
- Duke Molecular Physiology Institute, Duke University Medical Center
- Elbert Geuze
- Brain Research and Innovation Centre, Netherlands Ministry of Defence
- Gerald Grant
- Department of Neurosurgery, Duke University School of Medicine
- Michael A. Hauser
- Department of Medicine, Duke University School of Medicine
- Jasmeet P. Hayes
- Department of Psychology, The Ohio State University
- Sian M. J. Hemmings
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University
- Bertrand Russel Huber
- Department of Neurology, Boston University School of Medicine
- Aarti Jajoo
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
- Stefan Jansen
- College of Medicine and Health Sciences, University of Rwanda
- Ronald C. Kessler
- Department of Health Care Policy, Harvard Medical School
- Nathan A. Kimbrel
- Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine
- Anthony P. King
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine
- Joel E. Kleinman
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine
- Nastassja Koen
- Department of Psychiatry & Mental Health, University of Cape Town
- Karestan C. Koenen
- Department of Epidemiology, Harvard T.H. Chan School of Public Health
- Pei-Fen Kuan
- Department of Applied Mathematics and Statistics, Stony Brook University
- Israel Liberzon
- Department of Psychiatry and Behavioral Sciences, Texas A&M University College of Medicine
- Sarah D. Linnstaedt
- Department of Anesthesiology, University of North Carolina at Chapel Hill
- Adriana Lori
- Department of Psychiatry and Behavioral Sciences, Emory University
- Benjamin J. Luft
- Department of Medicine, Stony Brook University
- Jurjen J. Luykx
- Amsterdam Neuroscience Research Institute Stress & Sleep Program, Amsterdam University Medical Center
- Christine E. Marx
- Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine
- Samuel A. McLean
- Department of Psychiatry, UNC Institute for Trauma Recovery
- Divya Mehta
- Centre for Genomics and Personalised Health, Queensland University of Technology
- William Milberg
- GRECC/TRACTS, VA Boston Healthcare System
- Mark W. Miller
- Biomedical Genetics & Psychiatry, Boston University Chobanian & Avedisian School of Medicine
- Mary S. Mufford
- Department of Psychiatry and Mental Health, University of Cape Town
- Clarisse Musanabaganwa
- Research Innovation and Data Science Division, Rwanda Biomedical Center
- Jean Mutabaruka
- Department of Clinical Psychology, University of Rwanda
- Leon Mutesa
- College of Medicine and Health Sciences, University of Rwanda
- Charles B. Nemeroff
- Department of Psychology, The University of Texas at Austin
- Nicole R. Nugent
- Department of Emergency Medicine, Alpert Brown Medical School
- Holly K. Orcutt
- Department of Psychology, Northern Illinois University
- Xue-Jun Qin
- Duke Molecular Physiology Institute, Duke University
- Sheila A. M. Rauch
- Department of Psychiatry & Behavioral Sciences, Emory University
- Kerry J. Ressler
- Department of Psychiatry, Harvard Medical School
- Victoria B. Risbrough
- Department of Psychiatry, University of California San Diego
- Eugène Rutembesa
- Clinical Psychology, University of Rwanda
- Bart P. F. Rutten
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht Universitair Medisch Centrum
- Soraya Seedat
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University
- Dan J. Stein
- Department of Psychiatry & Mental Health, University of Cape Town
- Murray B. Stein
- Department of Psychiatry, University of California San Diego
- Sylvanus Toikumo
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University
- Robert J. Ursano
- Department of Psychiatry, Center for the Study of Traumatic Stress, Uniformed Services University
- Annette Uwineza
- College of Medicine and Health Sciences, University of Rwanda
- Mieke H. Verfaellie
- Department of Psychiatry, Boston University School of Medicine
- Eric Vermetten
- Department of Psychiatry, Leiden University Medical Center
- Christiaan H. Vinkers
- Department of Anatomy and Neurosciences, Amsterdam UMC Location Vrije Universiteit Amsterdam
- Erin B. Ware
- Survey Research Center, University of Michigan
- Derek E. Wildman
- College of Public Health, University of South Florida
- Erika J. Wolf
- National Center for PTSD, VA Boston Healthcare System
- Ross McD Young
- School of Clinical Sciences, Queensland University of Technology
- Ying Zhao
- Institute for Trauma Recovery, University of North Carolina at Chapel Hill
- Leigh L. van den Heuvel
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University
- PGC-PTSD Epigenetics Workgroup
- PsychENCODE PTSD Brainomics Project
- Traumatic Stress Brain Research Group
- Monica Uddin
- University of South Florida College of Public Health, Genomics Program
- Caroline M. Nievergelt
- Department of Psychiatry, University of California San Diego
- Alicia K. Smith
- Department of Gynecology and Obstetrics, Emory University
- Mark W. Logue
- Department of Biostatistics, Boston University School of Public Health
- DOI
- https://doi.org/10.1186/s13073-024-01417-1
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 17
Abstract
Abstract 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.
Keywords
