Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR

Alicia K. Smith; Andrew Ratanatharathorn; Adam X. Maihofer; Robert K. Naviaux; Allison E. Aiello; Ananda B. Amstadter; Allison E. Ashley-Koch; Dewleen G. Baker; Jean C. Beckham; Marco P. Boks; Evelyn Bromet; Michelle Dennis; Sandro Galea; Melanie E. Garrett; Elbert Geuze; Guia Guffanti; Michael A. Hauser; Seyma Katrinli; Varun Kilaru; Ronald C. Kessler; Nathan A. Kimbrel; Karestan C. Koenen; Pei-Fen Kuan; Kefeng Li; Mark W. Logue; Adriana Lori; Benjamin J. Luft; Mark W. Miller; Jane C. Naviaux; Nicole R. Nugent; Xuejun Qin; Kerry J. Ressler; Victoria B. Risbrough; Bart P. F. Rutten; Murray B. Stein; Robert J. Ursano; Eric Vermetten; Christiaan H. Vinkers; Lin Wang; Nagy A. Youssef; Monica Uddin; Caroline M. Nievergelt; INTRuST Clinical Consortium; VA Mid-Atlantic MIRECC Workgroup; PGC PTSD Epigenetics Workgroup

doi:10.1038/s41467-020-19615-x

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR

Alicia K. Smith^*, Andrew Ratanatharathorn, Adam X. Maihofer, Robert K. Naviaux, Allison E. Aiello, Ananda B. Amstadter, Allison E. Ashley-Koch, Dewleen G. Baker, Jean C. Beckham, Marco P. Boks, Evelyn Bromet, Michelle Dennis, Sandro Galea, Melanie E. Garrett, Elbert Geuze, Guia Guffanti, Michael A. Hauser, Seyma Katrinli, Varun Kilaru, Ronald C. KesslerNathan A. Kimbrel, Karestan C. Koenen, Pei-Fen Kuan, Kefeng Li, Mark W. Logue, Adriana Lori, Benjamin J. Luft, Mark W. Miller, Jane C. Naviaux, Nicole R. Nugent, Xuejun Qin, Kerry J. Ressler, Victoria B. Risbrough, Bart P. F. Rutten, Murray B. Stein, Robert J. Ursano, Eric Vermetten, Christiaan H. Vinkers, Lin Wang, Nagy A. Youssef, Monica Uddin, Caroline M. Nievergelt, INTRuST Clinical Consortium, VA Mid-Atlantic MIRECC Workgroup, PGC PTSD Epigenetics Workgroup

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	5965
Number of pages	9
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19615-x
Publication status	Published - 24 Nov 2020

Keywords

POSTTRAUMATIC-STRESS-DISORDER
ARYL-HYDROCARBON RECEPTOR
DNA METHYLATION
ASSOCIATION
IMMUNOLOGY
PROFILES
EXPOSURE
AGE

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10.1038/s41467-020-19615-xLicence: CC BY

Cite this

Smith, A. K., Ratanatharathorn, A., Maihofer, A. X., Naviaux, R. K., Aiello, A. E., Amstadter, A. B., Ashley-Koch, A. E., Baker, D. G., Beckham, J. C., Boks, M. P., Bromet, E., Dennis, M., Galea, S., Garrett, M. E., Geuze, E., Guffanti, G., Hauser, M. A., Katrinli, S., Kilaru, V., ... PGC PTSD Epigenetics Workgroup (2020). Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR. Nature Communications, 11(1), Article 5965. https://doi.org/10.1038/s41467-020-19615-x

@article{ef0028de74e84b509743ab2dc961ff4b,

title = "Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR",

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.",

keywords = "POSTTRAUMATIC-STRESS-DISORDER, ARYL-HYDROCARBON RECEPTOR, DNA METHYLATION, ASSOCIATION, IMMUNOLOGY, PROFILES, EXPOSURE, AGE",

author = "Smith, {Alicia K.} and Andrew Ratanatharathorn and Maihofer, {Adam X.} and Naviaux, {Robert K.} and Aiello, {Allison E.} and Amstadter, {Ananda B.} and Ashley-Koch, {Allison E.} and Baker, {Dewleen G.} and Beckham, {Jean C.} and Boks, {Marco P.} and Evelyn Bromet and Michelle Dennis and Sandro Galea and Garrett, {Melanie E.} and Elbert Geuze and Guia Guffanti and Hauser, {Michael A.} and Seyma Katrinli and Varun Kilaru and Kessler, {Ronald C.} and Kimbrel, {Nathan A.} and Koenen, {Karestan C.} and Pei-Fen Kuan and Kefeng Li and Logue, {Mark W.} and Adriana Lori and Luft, {Benjamin J.} and Miller, {Mark W.} and Naviaux, {Jane C.} and Nugent, {Nicole R.} and Xuejun Qin and Ressler, {Kerry J.} and Risbrough, {Victoria B.} and Rutten, {Bart P. F.} and Stein, {Murray B.} and Ursano, {Robert J.} and Eric Vermetten and Vinkers, {Christiaan H.} and Lin Wang and Youssef, {Nagy A.} and Monica Uddin and Nievergelt, {Caroline M.} and {INTRuST Clinical Consortium} and {VA Mid-Atlantic MIRECC Workgroup} and {PGC PTSD Epigenetics Workgroup}",

note = "Funding Information: This work was supported by the U.S. Army Medical Research and Materiel Command and the National Institute of Mental Health (NIMH; R01MH108826; R01MH106595), as well as the Biomedical and Laboratory Research and Development (#I01BX002577). We appreciate the technical support of all of the staff, volunteers and participants from the Grady Trauma Project, supported by the National Institutes of Mental Health (MH096764 and MH071537). DNHS, which is grateful to all of the participants and staff for their contributions, was funded by NIH Awards R01DA022720, R01DA022720-S1, and RC1MH088283. The Marine Corps, Navy Bureau of Medicine and Surgery (BUMED) and VA Health Research and Development (HSR&D) provided funding for MRS data collection and analysis and NIH R01MH093500 funded the GWAS assays and analysis. Acknowledged are Mark A. Geyer (UCSD), Daniel T. O{\textquoteright}Connor (UCSD), all MRS investigators, as well as the MRS administrative core and data collection staff listed in the Methods article59. We also thank the Marine and Navy Corpsmen volunteers for military service and participation in MRS. Support for metabolomics in the Naviaux lab at UCSD was provided in part by philanthropic gifts from the UCSD Christini Fund, the Lennox Foundation, the Wright Family Foundation, and the Jane Botsford Johnson Foundation. Data collection of PRISMO was funded by the Dutch Ministry of Defense, and DNA methylation analyses were funded by the VENI Award fellowship from the Netherlands Organization for Scientific Research (NWO, grant number 916.11.086). The VA Boston-National Center for PTSD Study research was supported in part by National Institute of Mental Health Award RO1MH079806, Department of Veterans Affairs, Clinical Science Research & Development Program Award 5I01CX000431-02, Department of Veterans Affairs, Biomedical Laboratory Research & Development Program Award 1I01BX002150-01. This research is the result of work supported with resources and the use of facilities at the Pharmacogenomics Analysis Laboratory, Research and Development Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. This work was also supported by a Career Development Award to E. J. Wolf from the Department of Veterans Affairs, Clinical Sciences Research, and Development Program. Dr. Kimbrel was supported by a Career Development Award (#IK2CX000525) from the Clinical Science Research and Development (CSR&D). Dr. Beckham was supported by a Research Career Scientist Award (#11S-RCS-009) from the CSR&D Service of VA ORD. This research was also supported, in part, by a Merit Award (#I01BX002577) from the Biomedical Laboratory Research and Development (BLR&D) Service of VA ORD. The VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup includes John A. Fairbank, Mira Brancu, Patrick S. Calhoun, Eric A. Dedert, Eric B. Elbogen, Kimberly T. Green, Robin A. Hurley, Angela C. Kirby, Jason D. Kilts, Christine E. Marx, Gregory McCarthy, Scott D. McDonald, Marinell Miller-Mumford, Scott D. Moore, Rajendra A. Morey, Jennifer C. Naylor, Treven C. Pickett, Jared Rowland, Jennifer J. Runnals, Cindy Swinkels, Steven T. Szabo, Katherine H. Taber, Larry A. Tupler, Elizabeth E. Van Voorhees, H. Ryan Wagner, Richard D. Weiner, and Ruth Yoash-Gantz. Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 (2009-2015) with the National Institutes of Health, National Institute of Mental Health (NIH/NIMH). WTC study was sponsored by CDC/NIOSH award U01 OH010416-01. The PTSD and TBI INjury and TRaUmatic STress Clinical Consortium (INTRuST) was funded by a grant from the United States Department of Defense: W81XWH08-2-0159. Members of the INTRuST Consortium Biorepository Working Group who contributed to this work include: Gerald A. Grant MD, Christine E. Marx MD, Mark S. George MD, Thomas W. McAllister MD, Norberto Andaluz MD, Lori Shutter MD, Raul Comibra MD, Ross D. Zafonte DO, Sonia Jain PhD, Xue-Jun Qin, and Michael Hauser PhD. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the VA, NIH, or the United States government. Funding Information: Dr. Youssef{\textquoteright}s disclosures include Speaker CME honoraria from the Georgia Department of Behavioral Health and Developmental Disabilities (DHBDD). Dr. Youssef received research support from the Department of Veteran Affairs and The Augusta Biomedical Research Corporation in the last 3 years. His current research funding (but not direct payment) include Merck pharmaceuticals (8S0073-9), and MECTA Corporation (72200S-2) and American Foundation for Suicide Prevention. Dr. Stein has in the past 3 years received payments for editorial work from UpToDate, Biological Psychiatry, and Depression and Anxiety. He has also in the past 3 years been paid as a consultant for Actelion Pharmaceuticals, Aptinyx, Bionomics, Janssen, and Pfizer. No other author declares any conflict of interest. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = nov,

day = "24",

doi = "10.1038/s41467-020-19615-x",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Smith, AK, Ratanatharathorn, A, Maihofer, AX, Naviaux, RK, Aiello, AE, Amstadter, AB, Ashley-Koch, AE, Baker, DG, Beckham, JC, Boks, MP, Bromet, E, Dennis, M, Galea, S, Garrett, ME, Geuze, E, Guffanti, G, Hauser, MA, Katrinli, S, Kilaru, V, Kessler, RC, Kimbrel, NA, Koenen, KC, Kuan, P-F, Li, K, Logue, MW, Lori, A, Luft, BJ, Miller, MW, Naviaux, JC, Nugent, NR, Qin, X, Ressler, KJ, Risbrough, VB, Rutten, BPF, Stein, MB, Ursano, RJ, Vermetten, E, Vinkers, CH, Wang, L, Youssef, NA, Uddin, M, Nievergelt, CM, INTRuST Clinical Consortium, VA Mid-Atlantic MIRECC Workgroup & PGC PTSD Epigenetics Workgroup 2020, 'Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR', Nature Communications, vol. 11, no. 1, 5965. https://doi.org/10.1038/s41467-020-19615-x

TY - JOUR

T1 - Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR

AU - Smith, Alicia K.

AU - Ratanatharathorn, Andrew

AU - Maihofer, Adam X.

AU - Naviaux, Robert K.

AU - Aiello, Allison E.

AU - Amstadter, Ananda B.

AU - Ashley-Koch, Allison E.

AU - Baker, Dewleen G.

AU - Beckham, Jean C.

AU - Boks, Marco P.

AU - Bromet, Evelyn

AU - Dennis, Michelle

AU - Galea, Sandro

AU - Garrett, Melanie E.

AU - Geuze, Elbert

AU - Guffanti, Guia

AU - Hauser, Michael A.

AU - Katrinli, Seyma

AU - Kilaru, Varun

AU - Kessler, Ronald C.

AU - Kimbrel, Nathan A.

AU - Koenen, Karestan C.

AU - Kuan, Pei-Fen

AU - Li, Kefeng

AU - Logue, Mark W.

AU - Lori, Adriana

AU - Luft, Benjamin J.

AU - Miller, Mark W.

AU - Naviaux, Jane C.

AU - Nugent, Nicole R.

AU - Qin, Xuejun

AU - Ressler, Kerry J.

AU - Risbrough, Victoria B.

AU - Rutten, Bart P. F.

AU - Stein, Murray B.

AU - Ursano, Robert J.

AU - Vermetten, Eric

AU - Vinkers, Christiaan H.

AU - Wang, Lin

AU - Youssef, Nagy A.

AU - Uddin, Monica

AU - Nievergelt, Caroline M.

AU - INTRuST Clinical Consortium

AU - VA Mid-Atlantic MIRECC Workgroup

AU - PGC PTSD Epigenetics Workgroup

N1 - Funding Information: This work was supported by the U.S. Army Medical Research and Materiel Command and the National Institute of Mental Health (NIMH; R01MH108826; R01MH106595), as well as the Biomedical and Laboratory Research and Development (#I01BX002577). We appreciate the technical support of all of the staff, volunteers and participants from the Grady Trauma Project, supported by the National Institutes of Mental Health (MH096764 and MH071537). DNHS, which is grateful to all of the participants and staff for their contributions, was funded by NIH Awards R01DA022720, R01DA022720-S1, and RC1MH088283. The Marine Corps, Navy Bureau of Medicine and Surgery (BUMED) and VA Health Research and Development (HSR&D) provided funding for MRS data collection and analysis and NIH R01MH093500 funded the GWAS assays and analysis. Acknowledged are Mark A. Geyer (UCSD), Daniel T. O’Connor (UCSD), all MRS investigators, as well as the MRS administrative core and data collection staff listed in the Methods article59. We also thank the Marine and Navy Corpsmen volunteers for military service and participation in MRS. Support for metabolomics in the Naviaux lab at UCSD was provided in part by philanthropic gifts from the UCSD Christini Fund, the Lennox Foundation, the Wright Family Foundation, and the Jane Botsford Johnson Foundation. Data collection of PRISMO was funded by the Dutch Ministry of Defense, and DNA methylation analyses were funded by the VENI Award fellowship from the Netherlands Organization for Scientific Research (NWO, grant number 916.11.086). The VA Boston-National Center for PTSD Study research was supported in part by National Institute of Mental Health Award RO1MH079806, Department of Veterans Affairs, Clinical Science Research & Development Program Award 5I01CX000431-02, Department of Veterans Affairs, Biomedical Laboratory Research & Development Program Award 1I01BX002150-01. This research is the result of work supported with resources and the use of facilities at the Pharmacogenomics Analysis Laboratory, Research and Development Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. This work was also supported by a Career Development Award to E. J. Wolf from the Department of Veterans Affairs, Clinical Sciences Research, and Development Program. Dr. Kimbrel was supported by a Career Development Award (#IK2CX000525) from the Clinical Science Research and Development (CSR&D). Dr. Beckham was supported by a Research Career Scientist Award (#11S-RCS-009) from the CSR&D Service of VA ORD. This research was also supported, in part, by a Merit Award (#I01BX002577) from the Biomedical Laboratory Research and Development (BLR&D) Service of VA ORD. The VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup includes John A. Fairbank, Mira Brancu, Patrick S. Calhoun, Eric A. Dedert, Eric B. Elbogen, Kimberly T. Green, Robin A. Hurley, Angela C. Kirby, Jason D. Kilts, Christine E. Marx, Gregory McCarthy, Scott D. McDonald, Marinell Miller-Mumford, Scott D. Moore, Rajendra A. Morey, Jennifer C. Naylor, Treven C. Pickett, Jared Rowland, Jennifer J. Runnals, Cindy Swinkels, Steven T. Szabo, Katherine H. Taber, Larry A. Tupler, Elizabeth E. Van Voorhees, H. Ryan Wagner, Richard D. Weiner, and Ruth Yoash-Gantz. Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 (2009-2015) with the National Institutes of Health, National Institute of Mental Health (NIH/NIMH). WTC study was sponsored by CDC/NIOSH award U01 OH010416-01. The PTSD and TBI INjury and TRaUmatic STress Clinical Consortium (INTRuST) was funded by a grant from the United States Department of Defense: W81XWH08-2-0159. Members of the INTRuST Consortium Biorepository Working Group who contributed to this work include: Gerald A. Grant MD, Christine E. Marx MD, Mark S. George MD, Thomas W. McAllister MD, Norberto Andaluz MD, Lori Shutter MD, Raul Comibra MD, Ross D. Zafonte DO, Sonia Jain PhD, Xue-Jun Qin, and Michael Hauser PhD. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the VA, NIH, or the United States government. Funding Information: Dr. Youssef’s disclosures include Speaker CME honoraria from the Georgia Department of Behavioral Health and Developmental Disabilities (DHBDD). Dr. Youssef received research support from the Department of Veteran Affairs and The Augusta Biomedical Research Corporation in the last 3 years. His current research funding (but not direct payment) include Merck pharmaceuticals (8S0073-9), and MECTA Corporation (72200S-2) and American Foundation for Suicide Prevention. Dr. Stein has in the past 3 years received payments for editorial work from UpToDate, Biological Psychiatry, and Depression and Anxiety. He has also in the past 3 years been paid as a consultant for Actelion Pharmaceuticals, Aptinyx, Bionomics, Janssen, and Pfizer. No other author declares any conflict of interest. Publisher Copyright: © 2020, The Author(s).

PY - 2020/11/24

Y1 - 2020/11/24

N2 - 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.

AB - 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.

KW - POSTTRAUMATIC-STRESS-DISORDER

KW - ARYL-HYDROCARBON RECEPTOR

KW - DNA METHYLATION

KW - ASSOCIATION

KW - IMMUNOLOGY

KW - PROFILES

KW - EXPOSURE

KW - AGE

U2 - 10.1038/s41467-020-19615-x

DO - 10.1038/s41467-020-19615-x

M3 - Article

C2 - 33235198

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5965

ER -