Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD

Alicia K Smith¹, Seyma Katrinli², Adam X Maihofer³, Allison E Aiello⁴, Dewleen G Baker⁵, Marco P Boks⁶, Leslie A Brick⁷, Chia-Yen Chen⁸, Shareefa Dalvie⁹, Negar Fani¹⁰, Catherine B Fortier¹¹, Joel Gelernter¹², Elbert Geuze¹³, Charles F Gillespie¹⁰, Jasmeet P Hayes¹⁴, Suzi Hong¹⁵, Ronald C Kessler¹⁶, Anthony P King¹⁷, Nastassja Koen¹⁸, Karestan C Koenen¹⁹, Israel Liberzon²⁰, Sarah D Linnstaedt²¹, Samuel A McLean²², Vasiliki Michopoulos¹⁰, William P Milberg¹¹, Mark W Miller²³, Mary S Mufford²⁴, Nicole R Nugent²⁵, Holly K Orcutt²⁶, Abigail Powers¹⁰, Sheila A M Rauch²⁷, Kerry J Ressler²⁸, Victoria B Risbrough³, Bart P F Rutten²⁹, Jordan W Smoller³⁰, Dan J Stein¹⁸, Murray B Stein³¹, Robert J Ursano³², Mieke H Verfaellie³³, Eric Vermetten³⁴, Christiaan H Vinkers³⁵, Agaz H Wani³⁶, Erin B WareVinkers³⁷, Derek E Wildman³⁸, Erika J Wolf²³, Ying Zhao²¹, Mark W Logue³⁹, Caroline M Nievergelt³, Monica Uddin³⁶, Anthony S Zannas⁴⁰; PGC-PTSD Epigenetics Workgroup; PsychENCODE PTSD Brainomics Project; Traumatic Stress Brain Research Group

Affiliations

¹ Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, USA; Emory University, Department of Human Genetics, Atlanta, GA, USA; Emory University, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA. Electronic address: alicia.smith@emory.edu.
² Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, USA.
³ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA; Veterans Affairs San Diego Healthcare System, Research Service, San Diego, CA, USA.
⁴ Columbia University, Robert N Butler Columbia Aging Center, Department of Epidemiology, New York, NY, USA.
⁵ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA.
⁶ Amsterdam UMC, Department of Psychiatry, Amsterdam, NH, Netherland; Dimence Specialised Mental Health, Mood Disorders, Deventer, OV, Netherland; University Medical Center Utrecht, Department Psychiatry, Utrecht, UT, Netherland.
⁷ Alpert Medical School of Brown University, Department of Psychiatry and Human Behavior, Providence, RI, USA.
⁸ Biogen Inc., Translational Medicine, Cambridge, MA, USA.
⁹ University of Cape Town, Division of Human Genetics, Cape Town, Western Province, South Africa.
¹⁰ Emory University, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA.
¹¹ Harvard Medical School, Department of Psychiatry, Boston, MA, USA; VA Boston Healthcare System, Geriatric Research, Education and Clinical Center (GRECC), Boston, MA, USA; VA Boston Healthcare System, Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS), Boston, MA, USA.
¹² VA Connecticut Healthcare Center, Psychiatry Service, West Haven, CT, USA; Yale University School of Medicine, Departments of Psychiatry, Genetics and Neuroscience, New Haven, CT, USA.
¹³ Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, UT, Netherland; UMC Utrecht Brain Center Rudolf Magnus, Department of Psychiatry, Utrecht, UT, Netherland.
¹⁴ The Ohio State University, Department of Psychology, Columbus, OH, USA.
¹⁵ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA; University of California San Diego, Herbert Wertheim School of Public Health and Human Longevity Science, La Jolla, CA, USA.
¹⁶ Harvard Medical School, Department of Health Care Policy, Boston, MA, USA.
¹⁷ The Ohio State University, College of Medicine, Institute for Behavioral Medicine Research, Columbus, OH, USA; The Ohio State University, College of Medicine, Psychiatry & Behavioral Health, Columbus, OH, USA.
¹⁸ University of Cape Town, Department of Psychiatry & Mental Health, Cape Town, Western Province, South Africa; University of Cape Town, Neuroscience Institute, Cape Town, Western Province, South Africa; University of Cape Town, SA MRC Unit on Risk & Resilience in Mental Disorders, Cape Town, Western Province, South Africa.
¹⁹ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA; Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA, USA; Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA.
²⁰ Texas A&M University College of Medicine, Department of Psychiatry and Behavioral Sciences, Bryan, TX, USA.
²¹ University of North Carolina at Chapel Hill, Department of Anesthesiology, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Institute for Trauma Recovery, Chapel Hill, NC, USA.
²² University of North Carolina at Chapel Hill, Institute for Trauma Recovery, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Department of Psychiatry, Chapel Hill, NC, USA.
²³ Boston University Chobanian & Avedisian School of Medicine, Department of Psychiatry, Boston, MA, USA; VA Boston Healthcare System, National Center for PTSD, Boston, MA, USA.
²⁴ University of Cape Town, Department of Psychiatry and Mental Health, Cape Town, Western Province, South Africa.
²⁵ Alpert Brown Medical School, Department of Emergency Medicine, Providence, RI, USA; Alpert Brown Medical School, Department of Pediatrics, Providence, RI, USA; Alpert Brown Medical School, Department of Psychiatry and Human Behavior, Providence, RI, USA.
²⁶ Northern Illinois University, Department of Psychology, DeKalb, IL, USA.
²⁷ Emory University School of Medicine, Department of Psychiatry & Behavioral Sciences, Atlanta, GA, USA; Joseph Maxwell Cleland Atlanta Veterans Affairs Healthcare System, Mental Health Service Line, Atlanta, GA, USA.
²⁸ Emory University, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA; Harvard Medical School, Department of Psychiatry, Boston, MA, USA; McLean Hospital, Division of Depression and Anxiety, Belmont, MA, USA.
²⁹ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA; Maastricht University, Department of Psychiatry and Neuropsychology, Maastricht, Limburg, Netherland.
³⁰ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA; Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA; Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA.
³¹ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA; University of California San Diego, School of Public Health, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA.
³² Uniformed Services University of Health Sciences, Center for the Study of Traumatic Stress, Department of Psychiatry, Bethesda, MD, USA.
³³ Boston University School of Medicine, Department of Psychiatry, Boston, MA, USA; VA Boston Healthcare System, Memory Disorders Research Center, Boston, MA, USA.
³⁴ Leiden University Medical Center, Department of Psychiatry, Leiden, ZH, Netherland; New York University School of Medicine, Department of Psychiatry, New York, NY, USA.
³⁵ Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Amsterdam, NH, Netherland; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam, Holland, Netherland; Amsterdam University Medical Center, Amsterdam Neuroscience Research Institute, Mood, Anxiety, Psychosis, Stress & Sleep Program, Amsterdam, NH, Netherland.
³⁶ University of South Florida College of Public Health, Genomics Program, Tampa, FL, USA.
³⁷ University of Michigan, Survey Research Center, Ann Arbor, MI, USA.
³⁸ Boston University Chobanian & Avedisian School of Medicine, Department of Biomedical Genetics, Boston, MA, USA.
³⁹ Boston University Chobanian & Avedisian School of Medicine, Department of Psychiatry, Boston, MA, USA; VA Boston Healthcare System, National Center for PTSD, Boston, MA, USA; Boston University School of Public Health, Department of Biostatistics, Boston, MA, USA; University of North Carolina at Chapel Hill, Carolina Stress Initiative, Chapel Hill, NC, USA.
⁴⁰ University of North Carolina at Chapel Hill, Institute for Trauma Recovery, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Department of Psychiatry, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Carolina Stress Initiative, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Department of Genetics, Chapel Hill, NC, USA.

PMID: 40286993
PMCID: PMC12286750 (available on 2026-04-24)
DOI: 10.1016/j.bbi.2025.04.031

Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD

Alicia K Smith et al. Brain Behav Immun. 2025 Aug.

. 2025 Aug:128:540-548.

doi: 10.1016/j.bbi.2025.04.031. Epub 2025 Apr 24.

Authors

Affiliations

¹ Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, USA; Emory University, Department of Human Genetics, Atlanta, GA, USA; Emory University, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA. Electronic address: alicia.smith@emory.edu.
² Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, USA.
³ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA; Veterans Affairs San Diego Healthcare System, Research Service, San Diego, CA, USA.
⁴ Columbia University, Robert N Butler Columbia Aging Center, Department of Epidemiology, New York, NY, USA.
⁵ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA.
⁶ Amsterdam UMC, Department of Psychiatry, Amsterdam, NH, Netherland; Dimence Specialised Mental Health, Mood Disorders, Deventer, OV, Netherland; University Medical Center Utrecht, Department Psychiatry, Utrecht, UT, Netherland.
⁷ Alpert Medical School of Brown University, Department of Psychiatry and Human Behavior, Providence, RI, USA.
⁸ Biogen Inc., Translational Medicine, Cambridge, MA, USA.
⁹ University of Cape Town, Division of Human Genetics, Cape Town, Western Province, South Africa.
¹⁰ Emory University, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA.
¹¹ Harvard Medical School, Department of Psychiatry, Boston, MA, USA; VA Boston Healthcare System, Geriatric Research, Education and Clinical Center (GRECC), Boston, MA, USA; VA Boston Healthcare System, Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS), Boston, MA, USA.
¹² VA Connecticut Healthcare Center, Psychiatry Service, West Haven, CT, USA; Yale University School of Medicine, Departments of Psychiatry, Genetics and Neuroscience, New Haven, CT, USA.
¹³ Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, UT, Netherland; UMC Utrecht Brain Center Rudolf Magnus, Department of Psychiatry, Utrecht, UT, Netherland.
¹⁴ The Ohio State University, Department of Psychology, Columbus, OH, USA.
¹⁵ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA; University of California San Diego, Herbert Wertheim School of Public Health and Human Longevity Science, La Jolla, CA, USA.
¹⁶ Harvard Medical School, Department of Health Care Policy, Boston, MA, USA.
¹⁷ The Ohio State University, College of Medicine, Institute for Behavioral Medicine Research, Columbus, OH, USA; The Ohio State University, College of Medicine, Psychiatry & Behavioral Health, Columbus, OH, USA.
¹⁸ University of Cape Town, Department of Psychiatry & Mental Health, Cape Town, Western Province, South Africa; University of Cape Town, Neuroscience Institute, Cape Town, Western Province, South Africa; University of Cape Town, SA MRC Unit on Risk & Resilience in Mental Disorders, Cape Town, Western Province, South Africa.
¹⁹ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA; Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA, USA; Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA.
²⁰ Texas A&M University College of Medicine, Department of Psychiatry and Behavioral Sciences, Bryan, TX, USA.
²¹ University of North Carolina at Chapel Hill, Department of Anesthesiology, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Institute for Trauma Recovery, Chapel Hill, NC, USA.
²² University of North Carolina at Chapel Hill, Institute for Trauma Recovery, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Department of Psychiatry, Chapel Hill, NC, USA.
²³ Boston University Chobanian & Avedisian School of Medicine, Department of Psychiatry, Boston, MA, USA; VA Boston Healthcare System, National Center for PTSD, Boston, MA, USA.
²⁴ University of Cape Town, Department of Psychiatry and Mental Health, Cape Town, Western Province, South Africa.
²⁵ Alpert Brown Medical School, Department of Emergency Medicine, Providence, RI, USA; Alpert Brown Medical School, Department of Pediatrics, Providence, RI, USA; Alpert Brown Medical School, Department of Psychiatry and Human Behavior, Providence, RI, USA.
²⁶ Northern Illinois University, Department of Psychology, DeKalb, IL, USA.
²⁷ Emory University School of Medicine, Department of Psychiatry & Behavioral Sciences, Atlanta, GA, USA; Joseph Maxwell Cleland Atlanta Veterans Affairs Healthcare System, Mental Health Service Line, Atlanta, GA, USA.
²⁸ Emory University, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA; Harvard Medical School, Department of Psychiatry, Boston, MA, USA; McLean Hospital, Division of Depression and Anxiety, Belmont, MA, USA.
²⁹ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA; Maastricht University, Department of Psychiatry and Neuropsychology, Maastricht, Limburg, Netherland.
³⁰ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA; Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA; Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA.
³¹ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA; University of California San Diego, School of Public Health, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA.
³² Uniformed Services University of Health Sciences, Center for the Study of Traumatic Stress, Department of Psychiatry, Bethesda, MD, USA.
³³ Boston University School of Medicine, Department of Psychiatry, Boston, MA, USA; VA Boston Healthcare System, Memory Disorders Research Center, Boston, MA, USA.
³⁴ Leiden University Medical Center, Department of Psychiatry, Leiden, ZH, Netherland; New York University School of Medicine, Department of Psychiatry, New York, NY, USA.
³⁵ Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Amsterdam, NH, Netherland; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam, Holland, Netherland; Amsterdam University Medical Center, Amsterdam Neuroscience Research Institute, Mood, Anxiety, Psychosis, Stress & Sleep Program, Amsterdam, NH, Netherland.
³⁶ University of South Florida College of Public Health, Genomics Program, Tampa, FL, USA.
³⁷ University of Michigan, Survey Research Center, Ann Arbor, MI, USA.
³⁸ Boston University Chobanian & Avedisian School of Medicine, Department of Biomedical Genetics, Boston, MA, USA.
³⁹ Boston University Chobanian & Avedisian School of Medicine, Department of Psychiatry, Boston, MA, USA; VA Boston Healthcare System, National Center for PTSD, Boston, MA, USA; Boston University School of Public Health, Department of Biostatistics, Boston, MA, USA; University of North Carolina at Chapel Hill, Carolina Stress Initiative, Chapel Hill, NC, USA.
⁴⁰ University of North Carolina at Chapel Hill, Institute for Trauma Recovery, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Department of Psychiatry, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Carolina Stress Initiative, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Department of Genetics, Chapel Hill, NC, USA.

PMID: 40286993
PMCID: PMC12286750 (available on 2026-04-24)
DOI: 10.1016/j.bbi.2025.04.031

Abstract

Background: Epigenetic modifications, including DNA methylation (DNAm), can change in response to traumatic stress exposure, and may help to distinguish between individuals with and without PTSD. Here, we examine the DNAm patterns specific to immune cell types and inflammation in those with PTSD.

Methods: This study includes 3,277 participants from 11 cohorts participating in the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. DNAm was assayed from blood with the MethylationEPIC BeadChip. A standardized QC pipeline was applied and used to impute cell composition. Within each cohort, we identified cell-type-specific DNAm patterns associated with PTSD, controlling for sex (if applicable), age, and ancestry. Meta-analyses were performed from summary statistics.

Results: PTSD cases had lower proportions of B cells and NK cells as well as higher proportions of neutrophils when compared to trauma-exposed controls. Overall, we identified 96 PTSD-associated CpGs across six types of immune cells. Most of these differences were identified in B cells, with 95 % exhibiting lower methylation levels in those with PTSD. Interestingly, the PTSD-associated CpGs annotated to a gene in B cells were enriched in a recent GWAS of PTSD (p < 0.0001).

Conclusions: This study identifies novel PTSD-associated CpGs in individual immune cell types and supports the role of immune dysregulation and inflammation in PTSD.

Keywords: B-cells; CRP; DNA methylation; EWAS; Immune; Inflammation; PTSD; Trauma.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chia-Yen Chen is an employee of Biogen. Dr. Koenen has done paid consulting for the US Department of Justice and Covington and Burling, LLP. She receives royalties from Oxford University Press and Guilford Press. Dr. McLean has served as a consultant for Walter Reed Army Institute for Research, Arbor Medical Innovations, and BioXcel Therapeutics, Inc. Dr. Nugent is an unpaid member of the scientific advisory board for Ilimivu. Dr. Rauch receives royalties from Oxford University Press and American Psychological Association Press and serves on the Advisory Panel for Otsuka Pharmaceuticals. Dr. Ressler has performed scientific consultation for Bioxcel, Bionomics, Acer, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, and the Brain Research Foundation, and he has received sponsored research support from Alto Neuroscience. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. All other authors declare no interests.

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Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD

Affiliations

Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Medical