Meta-Analysis

. 2024 Dec 18;16(1):147.

doi: 10.1186/s13073-024-01417-1.

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

Seyma Katrinli¹, Agaz H Wani², Adam X Maihofer^{3

4

5}, Andrew Ratanatharathorn^{6

7}, Nikolaos P Daskalakis^{8

9

10}, Janitza Montalvo-Ortiz^{11

12

13}, Diana L Núñez-Ríos^{11

12

13}, Anthony S Zannas^{14

15

16

17}, Xiang Zhao¹⁸, Allison E Aiello¹⁹, Allison E Ashley-Koch²⁰, Diana Avetyan³, Dewleen G Baker^{3

4

21}, Jean C Beckham^{22

23

24}, Marco P Boks²⁵, Leslie A Brick²⁶, Evelyn Bromet²⁷, Frances A Champagne²⁸, Chia-Yen Chen²⁹, Shareefa Dalvie^{30

31}, Michelle F Dennis^{22

23

24}, Segun Fatumo³², Catherine Fortier^{9

33}, Sandro Galea³⁴, Melanie E Garrett²⁰, Elbert Geuze^{35

36}, Gerald Grant³⁷, Michael A Hauser³⁸, Jasmeet P Hayes³⁹, Sian M J Hemmings^{40

41}, Bertrand Russel Huber^{42

43}, Aarti Jajoo^{8

9

44}, Stefan Jansen⁴⁵, Ronald C Kessler⁴⁶, Nathan A Kimbrel^{22

24

47}, Anthony P King^{48

49}, Joel E Kleinman^{50

51}, Nastassja Koen^{52

53

54}, Karestan C Koenen^{7

8

55}, Pei-Fen Kuan⁵⁶, Israel Liberzon⁵⁷, Sarah D Linnstaedt^{58

59}, Adriana Lori⁶⁰, Benjamin J Luft⁶¹, Jurjen J Luykx^{62

63

64}, Christine E Marx^{22

65

66}, Samuel A McLean⁶⁷, Divya Mehta^{68

69}, William Milberg⁷⁰, Mark W Miller^{71

72}, Mary S Mufford⁷³, Clarisse Musanabaganwa^{74

75}, Jean Mutabaruka⁷⁶, Leon Mutesa^{45

77}, Charles B Nemeroff^{28

78}, Nicole R Nugent^{79

80

81}, Holly K Orcutt⁸², Xue-Jun Qin⁸³, Sheila A M Rauch^{84

85}, Kerry J Ressler^{9

44

60}, Victoria B Risbrough^{3

4

5}, Eugène Rutembesa⁸⁶, Bart P F Rutten⁸⁷, Soraya Seedat^{40

88}, Dan J Stein^{52

53

54}, Murray B Stein^{3

21

89}, Sylvanus Toikumo^{40

90}, Robert J Ursano⁹¹, Annette Uwineza⁹², Mieke H Verfaellie^{93

94}, Eric Vermetten^{95

96}, Christiaan H Vinkers^{97

98

99}, Erin B Ware¹⁰⁰, Derek E Wildman^{101

102}, Erika J Wolf^{72

103}, Ross McD Young^{104

105}, Ying Zhao^{17

58}, Leigh L van den Heuvel^{40

88}; PGC-PTSD Epigenetics Workgroup; PsychENCODE PTSD Brainomics Project; Traumatic Stress Brain Research Group; Monica Uddin¹⁰⁶, Caroline M Nievergelt^{3

4

5}, Alicia K Smith^{1

60

107}, Mark W Logue^{108

109

110}

Collaborators, Affiliations

Collaborators

Reid S Alisch, Ananda B Amstadter, Don Armstrong, Archana Basu, Nicole L Bjorklund, Barbara H Chaiyachati, Judith B M Ensink, Leland L Fleming, Joel Gelernter, Ryan J Herringa, Sonia Jain, Diana L Juvinao-Quintero, Elizabeth Ketema, José J Martínez-Magaña, Burook Misganaw, Shiela Tiemi Nagamatsu, Danny M Nispeling, John Pfeiffer, Christian Schmahl, Gen Shinozaki, Clara Snijders, Jennifer A Sumner, Patricia C Swart, Audrey Tyrka, Mirjam van Zuiden, Jaqueline S Womersley, Nagy A Youssef, Yuanchao Zheng, Yiwen Zhu, Lea Zillich, Dhivya Arasappan, Sabina Berretta, Rahul A Bharadwaj, Leonardo Collado-Torres, Christos Chatzinakos, Chris P DiPietro, Duc M Duong, Amy Deep-Soboslay, Nick Eagles, Louise Huuki, Thomas Hyde, Artemis Iatrou, Geo Pertea, Deanna Ross, Nicholas T Seyfried, Joo Heon Shin, Victor E Alvarez, David Benedek, Alicia Che, Dianne A Cruz, David A Davis, Matthew J Girgenti, Ellen Hoffman, Paul E Holtzheimer, Alfred Kaye, John H Krystal, Adam T Labadorf, Terence M Keane, Ann McKee, Brian Marx, Crystal Noller, Meghan Pierce, William K Scott, Paula Schnurr, Krista DiSano, Thor Stein, Douglas E Williamson, Keith A Young

Affiliations

¹ Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA.
² Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA.
³ Department of Psychiatry, University of California San Diego, La Jolla, CA, San Diego, USA.
⁴ Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
⁵ Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
⁶ Department of Epidemiology, Columbia University Mailmain School of Public Health, New York, NY, USA.
⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
¹⁰ Center of Excellence in Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, USA.
¹¹ U.S. Department of Veterans Affairs National Center of Posttraumatic Stress Disorder, Clinical Neurosciences Division, West Haven, CT, USA.
¹² VA Connecticut Healthcare System, West Haven, CT, USA.
¹³ Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
¹⁴ Carolina Stress Initiative, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
¹⁵ Department of Genetics, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
¹⁶ Department of Psychiatry, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
¹⁷ Institute for Trauma Recovery, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
¹⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁹ Robert N. Butler Columbia Aging Center, Department of Epidemiology, Columbia University, New York, NY, USA.
²⁰ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
²¹ Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
²² Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA.
²³ Durham VA Health Care System, Researcg, Durham, NC, USA.
²⁴ Genetics Research Laboratory, VA Mid-Atlantic Mental Illness Research Education, and Clinical Center (MIRECC), Durham, NC, USA.
²⁵ Department of Psychiatry, Brain Center University Medical Center Utrecht, Utrecht, UT, NL, Netherlands.
²⁶ Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
²⁷ Epidemiology Research Group, State University of New York at Stony Brook, Stony Brook, NY, USA.
²⁸ Department of Psychology, The University of Texas at Austin, Austin, TX, USA.
²⁹ Biogen Inc, Translational Sciences, Cambridge, MA, USA.
³⁰ Department of Pathology, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
³¹ Division of Human Genetics, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
³² MRC/UVRI and London School of Hygiene and Tropical Medicine, The African Computational Genomics (TACG) Research Group, Entebbe, Wakiso, Uganda.
³³ Translational Research Center for TBI and Stress Disorders (TRACTS)/Geriatric Research Education and Clinical Center (GRECC), VA Boston Healthcare System, Boston, MA, USA.
³⁴ School of Public Health, Boston University, Boston, MA, USA.
³⁵ Brain Research and Innovation Centre, Netherlands Ministry of Defence, Utrecht, UT, NL, Netherlands.
³⁶ Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, UT, Netherlands.
³⁷ Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
³⁸ Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
³⁹ Department of Psychology, The Ohio State University, Columbus, OH, USA.
⁴⁰ Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Western Cape, Cape Town, ZA, South Africa.
⁴¹ SAMRC Genomics of Brain Disorders Research Unit, Stellenbosch University, Western Cape, Cape Town, ZA, South Africa.
⁴² Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁴³ Pathology and Laboratory Medicine, VA Boston Healthcare System, Boston, MA, USA.
⁴⁴ McLean Hospital, Belmont, MA, USA.
⁴⁵ College of Medicine and Health Sciences, University of Rwanda, Kigali, RW, Rwanda.
⁴⁶ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
⁴⁷ Mental Health Service Line, Durham VA Health Care System, Durham, NC, USA.
⁴⁸ Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA.
⁴⁹ Psychiatry & Behavioral Health, The Ohio State University College of Medicine, Columbus, OH, USA.
⁵⁰ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵¹ Lieber Institute for Brain Development, Baltimore, MD, USA.
⁵² Department of Psychiatry & Mental Health, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
⁵³ Neuroscience Institute, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
⁵⁴ SA MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
⁵⁵ Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA.
⁵⁶ Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA.
⁵⁷ Department of Psychiatry and Behavioral Sciences, Texas A&M University College of Medicine, Bryan, TX, USA.
⁵⁸ Department of Anesthesiology, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
⁵⁹ UNC Institute for Trauma Recovery, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
⁶⁰ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
⁶¹ Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
⁶² Amsterdam Neuroscience Research Institute Stress & Sleep Program, Amsterdam University Medical Center, Amsterdam, NH, Netherlands.
⁶³ Amsterdam Public Health Research Institute, Mental Health Program, Amsterdam University Medical Center, Amsterdam, NH, Netherlands.
⁶⁴ Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, NH, Netherlands.
⁶⁵ Durham VA Health Care System, Durham, NC, USA.
⁶⁶ VA Mid-Atlantic Mental Illness Research Education, and Clinical Center (MIRECC), Durham, NC, USA.
⁶⁷ Department of Psychiatry, UNC Institute for Trauma Recovery, NC, Chapel Hill, USA.
⁶⁸ Centre for Genomics and Personalised Health, Queensland University of Technology, Kelvin Grove, QLD, AU, Brisbane, Australia.
⁶⁹ School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, QLD, AU, Brisbane, Australia.
⁷⁰ GRECC/TRACTS, VA Boston Healthcare System, Boston, MA, USA.
⁷¹ Biomedical Genetics & Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁷² National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.
⁷³ Department of Psychiatry and Mental Health, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
⁷⁴ Research Innovation and Data Science Division, Rwanda Biomedical Center, Kigali, Rwanda.
⁷⁵ Center of Human Genetics, University of Rwanda, Kigali, RW, Rwanda.
⁷⁶ Department of Clinical Psychology, University of Rwanda, Huye, RW, Rwanda.
⁷⁷ Center for Human Genetics, University of Rwanda, Kigali, RW, Rwanda.
⁷⁸ Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin, Austin, TX, USA.
⁷⁹ Department of Emergency Medicine, Alpert Brown Medical School, Providence, RI, USA.
⁸⁰ Department of Pediatrics, Alpert Brown Medical School, Providence, RI, USA.
⁸¹ Department of Psychiatry and Human Behavior, Alpert Brown Medical School, Providence, RI, USA.
⁸² Department of Psychology, Northern Illinois University, DeKalb, IL, USA.
⁸³ Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
⁸⁴ Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA, USA.
⁸⁵ Joseph Maxwell Cleland Atlanta Veterans Affairs Healthcare System, Atlanta, GA, USA.
⁸⁶ Clinical Psychology, University of Rwanda, Kigali, RW, Rwanda.
⁸⁷ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht Universitair Medisch Centrum, Maastricht, Limburg, NL, Netherlands.
⁸⁸ SA MRC Extramural Genomics of Brain Disorders Research Unit, Stellenbosch University, Western Cape, Cape Town, ZA, South Africa.
⁸⁹ School of Public Health, University of California San Diego, CA, La Jolla, USA.
⁹⁰ SA MRC Genomics of Brain Disorders Research Unit, Stellenbosch University, Western Cape, Cape Town, ZA, South Africa.
⁹¹ Department of Psychiatry, Center for the Study of Traumatic Stress, Uniformed Services University, Bethesda, MD, USA.
⁹² College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda.
⁹³ Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
⁹⁴ Memory Disorders Research Center, VA Boston Healthcare System, Boston, MA, USA.
⁹⁵ Department of Psychiatry, Leiden University Medical Center, Leiden, ZH, NL, Netherlands.
⁹⁶ Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
⁹⁷ Department of Anatomy and Neurosciences, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Holland, Netherlands.
⁹⁸ Department of Psychiatry, Amsterdam, UMC Location Vrije Universiteit Amsterdam, Amsterdam, Holland, Netherlands.
⁹⁹ Amsterdam University Medical Center, Amsterdam Neuroscience Research Institute, Stress & Sleep Program, MoodPsychosisAmsterdam, Holland, AnxietyNL, Netherlands.
¹⁰⁰ Survey Research Center, University of Michigan, Ann Arbor, MI, USA.
¹⁰¹ College of Public Health, University of South Florida, Tampa, FL, USA.
¹⁰² Genomics Program, University of South Florida, Tampa, FL, USA.
¹⁰³ Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
¹⁰⁴ School of Clinical Sciences, Queensland University of Technology, Kelvin Grove, QLD, AU, Brisbane, Australia.
¹⁰⁵ University of the Sunshine Coast, The Chancellory Sippy Downs, QLD, AU, Buderim, Australia.
¹⁰⁶ University of South Florida College of Public Health, Genomics Program, Tampa, FL, USA.
¹⁰⁷ Department of Human Genetics, Emory University, Atlanta, GA, USA.
¹⁰⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. loguem@bu.edu.
¹⁰⁹ Biomedical Genetics & Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA. loguem@bu.edu.
¹¹⁰ National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA. loguem@bu.edu.

PMID: 39696436
PMCID: PMC11658418
DOI: 10.1186/s13073-024-01417-1

Meta-Analysis

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

Seyma Katrinli et al. Genome Med. 2024.

. 2024 Dec 18;16(1):147.

doi: 10.1186/s13073-024-01417-1.

Authors

Collaborators

Reid S Alisch, Ananda B Amstadter, Don Armstrong, Archana Basu, Nicole L Bjorklund, Barbara H Chaiyachati, Judith B M Ensink, Leland L Fleming, Joel Gelernter, Ryan J Herringa, Sonia Jain, Diana L Juvinao-Quintero, Elizabeth Ketema, José J Martínez-Magaña, Burook Misganaw, Shiela Tiemi Nagamatsu, Danny M Nispeling, John Pfeiffer, Christian Schmahl, Gen Shinozaki, Clara Snijders, Jennifer A Sumner, Patricia C Swart, Audrey Tyrka, Mirjam van Zuiden, Jaqueline S Womersley, Nagy A Youssef, Yuanchao Zheng, Yiwen Zhu, Lea Zillich, Dhivya Arasappan, Sabina Berretta, Rahul A Bharadwaj, Leonardo Collado-Torres, Christos Chatzinakos, Chris P DiPietro, Duc M Duong, Amy Deep-Soboslay, Nick Eagles, Louise Huuki, Thomas Hyde, Artemis Iatrou, Geo Pertea, Deanna Ross, Nicholas T Seyfried, Joo Heon Shin, Victor E Alvarez, David Benedek, Alicia Che, Dianne A Cruz, David A Davis, Matthew J Girgenti, Ellen Hoffman, Paul E Holtzheimer, Alfred Kaye, John H Krystal, Adam T Labadorf, Terence M Keane, Ann McKee, Brian Marx, Crystal Noller, Meghan Pierce, William K Scott, Paula Schnurr, Krista DiSano, Thor Stein, Douglas E Williamson, Keith A Young

Affiliations

¹ Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA.
² Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA.
³ Department of Psychiatry, University of California San Diego, La Jolla, CA, San Diego, USA.
⁴ Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
⁵ Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
⁶ Department of Epidemiology, Columbia University Mailmain School of Public Health, New York, NY, USA.
⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
¹⁰ Center of Excellence in Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, USA.
¹¹ U.S. Department of Veterans Affairs National Center of Posttraumatic Stress Disorder, Clinical Neurosciences Division, West Haven, CT, USA.
¹² VA Connecticut Healthcare System, West Haven, CT, USA.
¹³ Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
¹⁴ Carolina Stress Initiative, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
¹⁵ Department of Genetics, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
¹⁶ Department of Psychiatry, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
¹⁷ Institute for Trauma Recovery, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
¹⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁹ Robert N. Butler Columbia Aging Center, Department of Epidemiology, Columbia University, New York, NY, USA.
²⁰ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
²¹ Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
²² Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA.
²³ Durham VA Health Care System, Researcg, Durham, NC, USA.
²⁴ Genetics Research Laboratory, VA Mid-Atlantic Mental Illness Research Education, and Clinical Center (MIRECC), Durham, NC, USA.
²⁵ Department of Psychiatry, Brain Center University Medical Center Utrecht, Utrecht, UT, NL, Netherlands.
²⁶ Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
²⁷ Epidemiology Research Group, State University of New York at Stony Brook, Stony Brook, NY, USA.
²⁸ Department of Psychology, The University of Texas at Austin, Austin, TX, USA.
²⁹ Biogen Inc, Translational Sciences, Cambridge, MA, USA.
³⁰ Department of Pathology, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
³¹ Division of Human Genetics, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
³² MRC/UVRI and London School of Hygiene and Tropical Medicine, The African Computational Genomics (TACG) Research Group, Entebbe, Wakiso, Uganda.
³³ Translational Research Center for TBI and Stress Disorders (TRACTS)/Geriatric Research Education and Clinical Center (GRECC), VA Boston Healthcare System, Boston, MA, USA.
³⁴ School of Public Health, Boston University, Boston, MA, USA.
³⁵ Brain Research and Innovation Centre, Netherlands Ministry of Defence, Utrecht, UT, NL, Netherlands.
³⁶ Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, UT, Netherlands.
³⁷ Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
³⁸ Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
³⁹ Department of Psychology, The Ohio State University, Columbus, OH, USA.
⁴⁰ Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Western Cape, Cape Town, ZA, South Africa.
⁴¹ SAMRC Genomics of Brain Disorders Research Unit, Stellenbosch University, Western Cape, Cape Town, ZA, South Africa.
⁴² Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁴³ Pathology and Laboratory Medicine, VA Boston Healthcare System, Boston, MA, USA.
⁴⁴ McLean Hospital, Belmont, MA, USA.
⁴⁵ College of Medicine and Health Sciences, University of Rwanda, Kigali, RW, Rwanda.
⁴⁶ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
⁴⁷ Mental Health Service Line, Durham VA Health Care System, Durham, NC, USA.
⁴⁸ Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA.
⁴⁹ Psychiatry & Behavioral Health, The Ohio State University College of Medicine, Columbus, OH, USA.
⁵⁰ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵¹ Lieber Institute for Brain Development, Baltimore, MD, USA.
⁵² Department of Psychiatry & Mental Health, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
⁵³ Neuroscience Institute, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
⁵⁴ SA MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
⁵⁵ Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA.
⁵⁶ Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA.
⁵⁷ Department of Psychiatry and Behavioral Sciences, Texas A&M University College of Medicine, Bryan, TX, USA.
⁵⁸ Department of Anesthesiology, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
⁵⁹ UNC Institute for Trauma Recovery, University of North Carolina at Chapel Hill, NC, Chapel Hill, USA.
⁶⁰ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
⁶¹ Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
⁶² Amsterdam Neuroscience Research Institute Stress & Sleep Program, Amsterdam University Medical Center, Amsterdam, NH, Netherlands.
⁶³ Amsterdam Public Health Research Institute, Mental Health Program, Amsterdam University Medical Center, Amsterdam, NH, Netherlands.
⁶⁴ Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, NH, Netherlands.
⁶⁵ Durham VA Health Care System, Durham, NC, USA.
⁶⁶ VA Mid-Atlantic Mental Illness Research Education, and Clinical Center (MIRECC), Durham, NC, USA.
⁶⁷ Department of Psychiatry, UNC Institute for Trauma Recovery, NC, Chapel Hill, USA.
⁶⁸ Centre for Genomics and Personalised Health, Queensland University of Technology, Kelvin Grove, QLD, AU, Brisbane, Australia.
⁶⁹ School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, QLD, AU, Brisbane, Australia.
⁷⁰ GRECC/TRACTS, VA Boston Healthcare System, Boston, MA, USA.
⁷¹ Biomedical Genetics & Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁷² National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.
⁷³ Department of Psychiatry and Mental Health, University of Cape Town, Western Province, Cape Town, ZA, South Africa.
⁷⁴ Research Innovation and Data Science Division, Rwanda Biomedical Center, Kigali, Rwanda.
⁷⁵ Center of Human Genetics, University of Rwanda, Kigali, RW, Rwanda.
⁷⁶ Department of Clinical Psychology, University of Rwanda, Huye, RW, Rwanda.
⁷⁷ Center for Human Genetics, University of Rwanda, Kigali, RW, Rwanda.
⁷⁸ Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin, Austin, TX, USA.
⁷⁹ Department of Emergency Medicine, Alpert Brown Medical School, Providence, RI, USA.
⁸⁰ Department of Pediatrics, Alpert Brown Medical School, Providence, RI, USA.
⁸¹ Department of Psychiatry and Human Behavior, Alpert Brown Medical School, Providence, RI, USA.
⁸² Department of Psychology, Northern Illinois University, DeKalb, IL, USA.
⁸³ Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
⁸⁴ Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA, USA.
⁸⁵ Joseph Maxwell Cleland Atlanta Veterans Affairs Healthcare System, Atlanta, GA, USA.
⁸⁶ Clinical Psychology, University of Rwanda, Kigali, RW, Rwanda.
⁸⁷ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht Universitair Medisch Centrum, Maastricht, Limburg, NL, Netherlands.
⁸⁸ SA MRC Extramural Genomics of Brain Disorders Research Unit, Stellenbosch University, Western Cape, Cape Town, ZA, South Africa.
⁸⁹ School of Public Health, University of California San Diego, CA, La Jolla, USA.
⁹⁰ SA MRC Genomics of Brain Disorders Research Unit, Stellenbosch University, Western Cape, Cape Town, ZA, South Africa.
⁹¹ Department of Psychiatry, Center for the Study of Traumatic Stress, Uniformed Services University, Bethesda, MD, USA.
⁹² College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda.
⁹³ Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
⁹⁴ Memory Disorders Research Center, VA Boston Healthcare System, Boston, MA, USA.
⁹⁵ Department of Psychiatry, Leiden University Medical Center, Leiden, ZH, NL, Netherlands.
⁹⁶ Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
⁹⁷ Department of Anatomy and Neurosciences, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Holland, Netherlands.
⁹⁸ Department of Psychiatry, Amsterdam, UMC Location Vrije Universiteit Amsterdam, Amsterdam, Holland, Netherlands.
⁹⁹ Amsterdam University Medical Center, Amsterdam Neuroscience Research Institute, Stress & Sleep Program, MoodPsychosisAmsterdam, Holland, AnxietyNL, Netherlands.
¹⁰⁰ Survey Research Center, University of Michigan, Ann Arbor, MI, USA.
¹⁰¹ College of Public Health, University of South Florida, Tampa, FL, USA.
¹⁰² Genomics Program, University of South Florida, Tampa, FL, USA.
¹⁰³ Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
¹⁰⁴ School of Clinical Sciences, Queensland University of Technology, Kelvin Grove, QLD, AU, Brisbane, Australia.
¹⁰⁵ University of the Sunshine Coast, The Chancellory Sippy Downs, QLD, AU, Buderim, Australia.
¹⁰⁶ University of South Florida College of Public Health, Genomics Program, Tampa, FL, USA.
¹⁰⁷ Department of Human Genetics, Emory University, Atlanta, GA, USA.
¹⁰⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. loguem@bu.edu.
¹⁰⁹ Biomedical Genetics & Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA. loguem@bu.edu.
¹¹⁰ National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA. loguem@bu.edu.

PMID: 39696436
PMCID: PMC11658418
DOI: 10.1186/s13073-024-01417-1

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: DNA methylation; GWAS; Gene expression; PTSD; Postmortem brain; Trauma.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All studies were approved by the institutional review boards (IRBs) of each respective institution and carried out in accordance with The Code of Ethics of the Helsinki Declaration. The BEAR study was approved by the Lifespan Hospitals IRB. DNHS was approved by the IRB at the University of Michigan and the University of North Carolina at Chapel Hill. DCHS was approved by the Faculty of Health Sciences, Human Research Ethics Committee, University of Cape Town, by Stellenbosch University, and by the Western Cape Provincial Health Research committee. GTP was approved by the IRBs of Emory University School of Medicine and the Research Oversight Committee of Grady Memorial Hospital. NIU study was approved by the Northern Illinois University IRB. Shared Roots study was approved by the IRB of Stellenbosch University (HREC: N13/08/115). AURORA is approved by the Biomedical IRB at UNC Chapel Hill through the office of Human Research Ethics, the central IRB for all study sites. H3_Rwanda was approved by the IRB of the College of Medicine and Health Sciences at the University of Rwanda (No.370/CMHS/IRB/2020). WTC study was approved by the Committees on Research Involving Human Subjects at Stony Brook University. GMRFQUT was approved by the Human Research Ethics Committee of the Queensland University of Technology and Greenslopes Private Hospital. MRS was approved by the IRBs of the University of California San Diego, VA San Diego Research Service, and Naval Health Research Center. PRISMO was approved by the IRB of the University Medical Center Utrecht. Army STARRS was approved by the Human Subjects Committees of the Uniformed Services University of the Health Sciences for the Henry M. Jackson Foundation (the primary grantee), the Institute for Social Research at the University of Michigan (the organization collecting the data), and all other collaborating organizations. PROGrESS was approved by the IRBs at VA Ann Arbor Healthcare System, the University of Michigan, Ralph H. Johnson VA Medical Center, VA San Diego Healthcare System, Massachusetts General Hospital, and the Department of Defense Human Research Protection Office. NCPTSD/TRACTS was approved by the IRBs of Human Studies Research at the VA Boston Healthcare System. INTRuST was approved by the Human Research Protection Program at the University of California San Diego. VA-M-AA and VA-M-EA were approved by the IRBs at the Salisbury VA, Hampton VA, Durham VA, and Duke University Medical Centers. All individuals provided written informed consent to participate in these studies. Consent for publication: Not applicable. Competing interests: CYC is an employee of Biogen Inc. NPD has served on scientific advisory boards for BioVie Pharma, Circular Genomics, and Sentio Solutions for unrelated work. NRN serves as an unpaid member of the Ilumivu advisory board. SAMR receives support from the Wounded Warrior Project (WWP), Department of Veterans Affairs (VA), National Institute of Health (NIH), McCormick Foundation, Tonix Pharmaceuticals, Woodruff Foundation, and Department of Defense (DOD). Dr. Rauch receives royalties from Oxford University Press and American. KJR serves as a consultant for Acer, Bionomics, and Jazz Pharma; SABs for Sage, Boehringer Ingelheim, and Senseye. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. MBS has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, BigHealth, Biogen, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio, Delix Therapeutics, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. MBS has stock options in Oxeia Biopharmaceuticals and EpiVario. MBS has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). MBS has also received research support from NIH, the Department of Veterans Affairs, and the Department of Defense. MBS is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America.

Figures

**Fig. 1**
Manhattan plot of the epigenome-wide association meta-analyses. The x-axis depicts chromosomes and the location of each CpG site across the genome. The y-axis depicts the − log10 of the unadjusted p-value for the association with current PTSD. Each dot represents a CpG site. The solid blue line indicates the epigenome‐wide statistical significance at p < 9.0e − 8

**Fig. 2**
Summary of all analyses and findings. The figure combines CpGs from the main analysis (gold) and stratified analyses for sex, ancestry, and trauma type (light gold); and summarizes the results of blood and brain correlations (rose); gene expression (purple); cross-tissue associations for multiple brain regions (light blue), neuronal nuclei (blue), and a fibroblast model of prolonged stress (aqua); and genetic effects, including methylation quantitative trait loci (meQTL) analyses (light green) and genetic associations from the recent PGC-PTSD GWAS (dark green). Positive findings (p < 0.05) are indicated with the specific color of the respective category. Asterisk (*) indicates epigenome-wide significance (p < 9e − 8). Gray represents the CpGs or genes that were not present in the respective datasets. PFC, prefrontal cortex; EC, entorhinal cortex; STG, superior temporal gyrus; CER, cerebellum; dlPFC, dorsolateral prefrontal cortex; vmPFC, ventromedial prefrontal cortex; DG, dentate gyrus; 5mC, 5-methylcytosine; GC, glucocorticoid

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Update of

Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts.
Katrinli S, Wani AH, Maihofer AX, Ratanatharathorn A, Daskalakis NP, Montalvo-Ortiz J, Núñez-Ríos DL, Zannas AS, Zhao X, Aiello AE, Ashley-Koch AE, Avetyan D, Baker DG, Beckham JC, Boks MP, Brick LA, Bromet E, Champagne FA, Chen CY, Dalvie S, Dennis MF, Fatumo S, Fortier C, Galea S, Garrett ME, Geuze E, Grant G, Michael A Hauser, Hayes JP, Hemmings SM, Huber BR, Jajoo A, Jansen S, Kessler RC, Kimbrel NA, King AP, Kleinman JE, Koen N, Koenen KC, Kuan PF, Liberzon I, Linnstaedt SD, Lori A, Luft BJ, Luykx JJ, Marx CE, McLean SA, Mehta D, Milberg W, Miller MW, Mufford MS, Musanabaganwa C, Mutabaruka J, Mutesa L, Nemeroff CB, Nugent NR, Orcutt HK, Qin XJ, Rauch SAM, Ressler KJ, Risbrough VB, Rutembesa E, Rutten BPF, Seedat S, Stein DJ, Stein MB, Toikumo S, Ursano RJ, Uwineza A, Verfaellie MH, Vermetten E, Vinkers CH, Ware EB, Wildman DE, Wolf EJ, Young RM, Zhao Y, van den Heuvel LL; PGC-PTSD Epigenetics Workgroup, PsychENCODE PTSD Brainomics Project, Traumatic Stress Brain Research Group; Uddin M, Nievergelt CM, Smith AK, Logue MW. Katrinli S, et al. medRxiv [Preprint]. 2024 Jul 15:2024.07.15.24310422. doi: 10.1101/2024.07.15.24310422. medRxiv. 2024. Update in: Genome Med. 2024 Dec 18;16(1):147. doi: 10.1186/s13073-024-01417-1. PMID: 39072012 Free PMC article. Updated. Preprint.

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

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

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