Abstract

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

PTSD has been associated with DNA methylation of specific loci in the genome, but studies have been limited by small sample sizes. Here, the authors perform a meta-analysis of DNA methylation data from 10 different cohorts and identify CpGs in AHRR that are associated with PTSD.

Details

Title
Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR
Author
Smith, Alicia K 1   VIAFID ORCID Logo  ; Ratanatharathorn, Andrew 2   VIAFID ORCID Logo  ; Maihofer, Adam X 3   VIAFID ORCID Logo  ; Naviaux, Robert K 4 ; Aiello, Allison E 5 ; Amstadter, Ananda B 6 ; Ashley-Koch, Allison E 7   VIAFID ORCID Logo  ; Baker, Dewleen G 8   VIAFID ORCID Logo  ; Beckham, Jean C 9 ; Boks, Marco P 10 ; Bromet Evelyn 11 ; Dennis, Michelle 12 ; Galea Sandro 13   VIAFID ORCID Logo  ; Garrett, Melanie E 7 ; Geuze Elbert 14   VIAFID ORCID Logo  ; Guffanti Guia 15 ; Hauser, Michael A 16 ; Katrinli Seyma 17   VIAFID ORCID Logo  ; Kilaru Varun 17 ; Kessler, Ronald C 18   VIAFID ORCID Logo  ; Kimbrel, Nathan A 9 ; Koenen, Karestan C 19 ; Kuan Pei-Fen 20   VIAFID ORCID Logo  ; Li, Kefeng 21   VIAFID ORCID Logo  ; Logue, Mark W 22 ; Adriana, Lori 23 ; Luft, Benjamin J 24   VIAFID ORCID Logo  ; Miller, Mark W 25   VIAFID ORCID Logo  ; Naviaux, Jane C 26 ; Nugent, Nicole R 27 ; Qin Xuejun 7   VIAFID ORCID Logo  ; Ressler, Kerry J 28   VIAFID ORCID Logo  ; Risbrough, Victoria B 8   VIAFID ORCID Logo  ; Rutten Bart P F 29   VIAFID ORCID Logo  ; Stein, Murray B 30   VIAFID ORCID Logo  ; Ursano, Robert J 31   VIAFID ORCID Logo  ; Vermetten Eric 32   VIAFID ORCID Logo  ; Vinkers, Christiaan H 33   VIAFID ORCID Logo  ; Wang, Lin 21 ; Youssef, Nagy A 34   VIAFID ORCID Logo  ; Marx, Christine 9 ; Grant, Gerry 35 ; Stein, Murray 30   VIAFID ORCID Logo  ; Xue-Jun, Qin 7 ; Jain, Sonia 36 ; McAllister, Thomas W 37 ; Zafonte Ross 38 ; Lang, Ariel 3 ; Coimbra Raul 39 ; Andaluz Norberto 40 ; Shutter, Lori 41 ; George, Mark S 42 ; Brancu Mira 43 ; Calhoun, Patrick S 44 ; Dedert Eric 44 ; Elbogen, Eric B 44 ; Fairbank, John A 44 ; Hurley, Robin A 45 ; Kilts, Jason D 46 ; Kirby, Angela 47 ; Marx, Christine E 44 ; McDonald, Scott D 48 ; Moore, Scott D 49 ; Morey, Rajendra A 44 ; Naylor, Jennifer C 44 ; Rowland, Jared A 50 ; Swinkels, Cindy 51 ; Szabo, Steven T 44 ; Taber, Katherine H 52 ; Tupler, Larry A 53 ; Van Voorhees Elizabeth E 44 ; Yoash-Gantz, Ruth E 50 ; Basu Archana 54 ; Brick, Leslie A 27 ; Dalvie Shareefa 55 ; Daskalakis, Nikolaos P 56 ; Ensink Judith B M 57 ; Hemmings Sian M J 58 ; Ryan, Herringa 59 ; Ikiyo Sylvanus 60 ; Nastassja, Koen 55 ; Kuan, Pei Fen 20 ; Montalvo-Ortiz Janitza 61 ; Nispeling Danny 10 ; Pfeiffer, John 62 ; Qin XueJun 7   VIAFID ORCID Logo  ; Schijven Dick 10 ; Seedat Soraya 58 ; Shinozaki Gen 63 ; Sumner, Jennifer A 64 ; Swart, Patricia 65 ; Tyrka Audrey 66 ; Van Zuiden Mirjam 67 ; Wani Agaz 68 ; Wolf, Erika J 25 ; Zannas Anthony 69 ; Uddin, Monica 68 ; Nievergelt, Caroline M 8 

1  Emory University, Department of Gynecology and Obstetrics, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502); Emory University, Department of Psychiatry & Behavioral Sciences, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
2  Columbia University, Department of Epidemiology, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
3  University of California San Diego, Department of Psychiatry, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
4  University of California, The Mitochondrial and Metabolic Disease Center, Departments of Medicine, Pediatrics, and Pathology, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
5  University of North Carolina, Gillings School of Global Public Health, Department of Epidemiology, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
6  Virginia Commonwealth University, Department of Psychiatry, Richmond, USA (GRID:grid.224260.0) (ISNI:0000 0004 0458 8737) 
7  Duke University Medical Center, Duke Molecular Physiology Institute, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216) 
8  University of California San Diego, Department of Psychiatry, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); Veterans Affairs San Diego Healthcare System, San Diego, USA (GRID:grid.410371.0) (ISNI:0000 0004 0419 2708); Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, USA (GRID:grid.410371.0) 
9  VA Mid-Atlantic, Mental Illness Research, Education, and Clinical Center, Durham, USA (GRID:grid.281208.1) (ISNI:0000 0004 0419 3073); Veterans Affairs Durham Healthcare System, Durham, USA (GRID:grid.281208.1); Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216) 
10  University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352) 
11  State University of New York at Stony Brook, Epidemiology Research Group, Stony Brook, USA (GRID:grid.36425.36) (ISNI:0000 0001 2216 9681) 
12  VA Mid-Atlantic, Mental Illness Research, Education, and Clinical Center, Durham, USA (GRID:grid.281208.1) (ISNI:0000 0004 0419 3073); Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216) 
13  Boston University, School of Public Health, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
14  University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352); Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, The Netherlands (GRID:grid.7692.a) 
15  McLean Hospital, Division of Depression and Anxiety, Belmont, USA (GRID:grid.240206.2) (ISNI:0000 0000 8795 072X); Harvard Medical School, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
16  Duke University Medical Center, Duke Molecular Physiology Institute, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216); Duke University, Department of Medicine, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
17  Emory University, Department of Gynecology and Obstetrics, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
18  Harvard Medical School, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
19  Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Department of Psychiatry, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, USA (GRID:grid.66859.34) 
20  State University of New York at Stony Brook, Department of Applied Mathematics and Statistics, Stony Brook, USA (GRID:grid.36425.36) (ISNI:0000 0001 2216 9681) 
21  University of California, The Mitochondrial and Metabolic Disease Center, Department of Medicine, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
22  National Center for PTSD, Behavioral Science Division at VA Boston Healthcare System, Boston, USA (GRID:grid.410370.1) (ISNI:0000 0004 4657 1992); Boston University School of Medicine, Department of Psychiatry, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Boston University School of Medicine, Department of Medicine (Biomedical Genetics), Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Boston University School of Public Health, Department of Biostatistics, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
23  Emory University, Department of Psychiatry & Behavioral Sciences, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
24  State University of New York at Stony Brook, Department of Medicine, Stony Brook, USA (GRID:grid.36425.36) (ISNI:0000 0001 2216 9681) 
25  National Center for PTSD, Behavioral Science Division at VA Boston Healthcare System, Boston, USA (GRID:grid.410370.1) (ISNI:0000 0004 4657 1992); Boston University School of Medicine, Department of Psychiatry, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
26  University of California, The Mitochondrial and Metabolic Disease Center, Department of Neuroscience, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
27  Brown University, Psychiatry and Human Behavior, Department of Pediatric Research, Providence, USA (GRID:grid.40263.33) (ISNI:0000 0004 1936 9094) 
28  Emory University, Department of Psychiatry & Behavioral Sciences, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502); McLean Hospital, Division of Depression and Anxiety, Belmont, USA (GRID:grid.240206.2) (ISNI:0000 0000 8795 072X); Harvard Medical School, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
29  Maastricht University Medical Centre, School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht, The Netherlands (GRID:grid.410371.0) 
30  University of California San Diego, Department of Psychiatry, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); Veterans Affairs San Diego Healthcare System, San Diego, USA (GRID:grid.410371.0) (ISNI:0000 0004 0419 2708); University of California San Diego, Department of Family Medicine and Public Health, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
31  Uniformed Services University School of Medicine, Center for the Study of Traumatic Stress, Bethesda, USA (GRID:grid.265436.0) (ISNI:0000 0001 0421 5525) 
32  University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352); Uniformed Services University School of Medicine, Center for the Study of Traumatic Stress, Bethesda, USA (GRID:grid.265436.0) (ISNI:0000 0001 0421 5525); Leiden University Medical Center, Department of Psychiatry, Leiden, The Netherlands (GRID:grid.10419.3d) (ISNI:0000000089452978); Netherlands Defense Department, Research Center, Utrecht, The Netherlands (GRID:grid.10419.3d); Arq Psychotrauma Expert Group, Diemen, The Netherlands (GRID:grid.491097.2) 
33  Amsterdam UMC (location VUmc), Department of Psychiatry, Amsterdam, The Netherlands (GRID:grid.491097.2); Amsterdam UMC (location VUmc), Department of Anatomy and Neurosciences, Amsterdam, The Netherlands (GRID:grid.16872.3a) (ISNI:0000 0004 0435 165X) 
34  Medical College of Georgia at Augusta University, Department of Psychiatry and Human Behavior and Office of Academic Affairs, Augusta, USA (GRID:grid.410427.4) (ISNI:0000 0001 2284 9329) 
35  Stanford University Medical Center, Department of Neurosurgery, Stanford, USA (GRID:grid.240952.8) (ISNI:0000000087342732) 
36  University of California San Diego, Department of Family Medicine and Public Health, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
37  Indiana University, Department of Psychiatry, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919) 
38  Spaulding Rehabilitation Hospital and Harvard Medical School, Charleston, USA (GRID:grid.416228.b) (ISNI:0000 0004 0451 8771) 
39  Riverside University Health System Medical Center, Moreno Valley, USA (GRID:grid.488519.9) (ISNI:0000 0004 5946 0028) 
40  University of Louisville School of Medicine, Louisville, USA (GRID:grid.266623.5) (ISNI:0000 0001 2113 1622) 
41  University of Pittsburgh School of Medicine, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
42  Medical University of South Carolina, Ralph H. Johnson VA Medical Center, Charleston, USA (GRID:grid.21925.3d) 
43  Veterans Affairs Durham Healthcare System, Durham, USA (GRID:grid.21925.3d); Duke University, Department of Medicine, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
44  Veterans Affairs Durham Healthcare System, Durham, USA (GRID:grid.26009.3d); Duke University, Department of Medicine, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
45  Salisbury Veterans Affairs Health Care System, Salisbury, USA (GRID:grid.26009.3d); Wake Forest University, Winston-Salem, USA (GRID:grid.241167.7) (ISNI:0000 0001 2185 3318); Baylor College of Medicine, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
46  Veterans Affairs Durham Healthcare System, Durham, USA (GRID:grid.39382.33); Duke University, Department of Medicine, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
47  Veterans Affairs Durham Healthcare System, Durham, USA (GRID:grid.26009.3d) 
48  Virginia Commonwealth University, Department of Psychiatry, Richmond, USA (GRID:grid.224260.0) (ISNI:0000 0004 0458 8737); Richmond Veterans Affairs Health Care System, Richmond, USA (GRID:grid.224260.0) 
49  Veterans Affairs Durham Healthcare System, Durham, USA (GRID:grid.224260.0); Duke University, Department of Medicine, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
50  Salisbury Veterans Affairs Health Care System, Salisbury, USA (GRID:grid.26009.3d); Wake Forest University, Winston-Salem, USA (GRID:grid.241167.7) (ISNI:0000 0001 2185 3318) 
51  Veterans Affairs Durham Healthcare System, Durham, USA (GRID:grid.241167.7); Duke University, Department of Medicine, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
52  Salisbury Veterans Affairs Health Care System, Salisbury, USA (GRID:grid.26009.3d); Baylor College of Medicine, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X); Virginia College of Osteopathic Medicine, Blacksburg, USA (GRID:grid.418737.e) (ISNI:0000 0000 8550 1509) 
53  Veterans Affairs Durham Healthcare System, Durham, USA (GRID:grid.418737.e); Duke University, Department of Medicine, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
54  Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
55  University of Cape Town, SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, Cape Town, South Africa (GRID:grid.7836.a) (ISNI:0000 0004 1937 1151) 
56  Harvard Medical School, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Cohen Veterans Bioscience, Cambridge, USA (GRID:grid.507100.3) (ISNI:0000 0004 6004 8305); Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
57  University of Amsterdam, Department of Child and Adolescent Psychiatry, Amsterdam Public Health Research Institute, Amsterdam UMC, Location Academic Medical Center, Amsterdam, The Netherlands (GRID:grid.59734.3c); Academic Center for Child and Adolescent Psychiatry, De Bascule, Amsterdam, The Netherlands (GRID:grid.491096.3); University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health Research Institute, Amsterdam UMC, Location Academic Medical Center, Amsterdam, The Netherlands (GRID:grid.491096.3) 
58  Stellenbosch University Faculty of Medicine and Health Sciences, Department of Psychiatry, Cape Town, South Africa (GRID:grid.11956.3a) (ISNI:0000 0001 2214 904X) 
59  University of Wisconsin School of Medicine and Public Health, Department of Psychiatry, Madison, USA (GRID:grid.471391.9) 
60  University of Aberdeen, Department of Applied Medicine, Aberdeen, UK (GRID:grid.7107.1) (ISNI:0000 0004 1936 7291) 
61  Yale University School of Medicine, Division of Human Genetics, Department of Psychiatry, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); VA CT Healthcare Center, West Haven, USA (GRID:grid.47100.32) 
62  University of Illinois at Urbana-Champaign, Department of Psychology, Urbana, USA (GRID:grid.35403.31) (ISNI:0000 0004 1936 9991) 
63  University of Iowa Carver College of Medicine, University of Iowa Hospitals and Clinics, Department of Psychiatry, Iowa City, USA (GRID:grid.11956.3a) 
64  Columbia University Medical Center, Department of Medicine, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
65  University of Cape Town, Department of Human Biology, Cape Town, South Africa (GRID:grid.7836.a) (ISNI:0000 0004 1937 1151) 
66  Brown University, Psychiatry and Human Behavior, Department of Pediatric Research, Providence, USA (GRID:grid.40263.33) (ISNI:0000 0004 1936 9094); Butler Hospital, Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Providence, USA (GRID:grid.273271.2) (ISNI:0000 0000 8593 9332) 
67  Amsterdam UMC (location VUmc), Department of Psychiatry, Amsterdam, The Netherlands (GRID:grid.273271.2) 
68  University of South Florida, College of Public Health, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
69  Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216); University of North Carolina, Department of Psychiatry, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720); University of North Carolina, Department of Genetics, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720); University of North Carolina School of Medicine, Institute for Trauma Recovery, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208); University of North Carolina, Neuroscience Curriculum, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-19615-x
ProQuest document ID
2473222332
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.