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; Christine Marx; Gerry Grant; Murray Stein; Xue Jun Qin; Sonia Jain; Thomas W. McAllister; Ross Zafonte; Ariel Lang; Raul Coimbra; Norberto Andaluz; Lori Shutter; Mark S. George; Mira Brancu; Patrick S. Calhoun; Eric Dedert; Eric B. Elbogen; John A. Fairbank; Robin A. Hurley; Jason D. Kilts; Angela Kirby; Christine E. Marx; Scott D. McDonald; Scott D. Moore; Rajendra A. Morey; Jennifer C. Naylor; Jared A. Rowland; Cindy Swinkels; Steven T. Szabo; Katherine H. Taber; Larry A. Tupler; Elizabeth E. Van Voorhees; Ruth E. Yoash-Gantz; Archana Basu; Leslie A. Brick; Shareefa Dalvie; Nikolaos P. Daskalakis; Judith B.M. Ensink; Sian M.J. Hemmings; Ryan Herringa; Sylvanus Ikiyo; Nastassja Koen; Pei Fen Kuan; Janitza Montalvo-Ortiz; Danny Nispeling; John Pfeiffer; Xue Jun Qin; Kerry J. Ressler; Dick Schijven; Soraya Seedat; Gen Shinozaki; Jennifer A. Sumner; Patricia Swart; Audrey Tyrka; Mirjam Van Zuiden; Agaz Wani; Erika J. Wolf; Anthony Zannas; 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, Christine Marx, Gerry Grant, Murray Stein, Xue Jun Qin, Sonia Jain, Thomas W. McAllister, Ross Zafonte, Ariel Lang, Raul Coimbra, Norberto Andaluz, Lori Shutter, Mark S. George, Mira Brancu, Patrick S. Calhoun, Eric Dedert, Eric B. Elbogen, John A. Fairbank, Robin A. Hurley, Jason D. Kilts, Angela Kirby, Christine E. Marx, Scott D. McDonald, Scott D. Moore, Rajendra A. Morey, Jennifer C. Naylor, Jared A. Rowland, Cindy Swinkels, Steven T. Szabo, Katherine H. Taber, Larry A. Tupler, Elizabeth E. Van Voorhees, Ruth E. Yoash-Gantz, Archana Basu, Leslie A. Brick, Shareefa Dalvie, Nikolaos P. Daskalakis, Judith B.M. Ensink, Sian M.J. Hemmings, Ryan Herringa, Sylvanus Ikiyo, Nastassja Koen, Pei Fen Kuan, Janitza Montalvo-Ortiz, Danny Nispeling, John Pfeiffer, Xue Jun Qin, Kerry J. Ressler, Dick Schijven, Soraya Seedat, Gen Shinozaki, Jennifer A. Sumner, Patricia Swart, Audrey Tyrka, Mirjam Van Zuiden, Agaz Wani, Erika J. Wolf, Anthony Zannas, 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.

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

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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), [5965]. https://doi.org/10.1038/s41467-020-19615-x

@article{6f27cef65fd34b73a221f075304e4f1e,

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.",

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 Kuan, {Pei Fen} 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 Christine Marx and Gerry Grant and Murray Stein and Qin, {Xue Jun} and Sonia Jain and McAllister, {Thomas W.} and Ross Zafonte and Ariel Lang and Raul Coimbra and Norberto Andaluz and Lori Shutter and George, {Mark S.} and Mira Brancu and Calhoun, {Patrick S.} and Eric Dedert and Elbogen, {Eric B.} and Fairbank, {John A.} and Hurley, {Robin A.} and Kilts, {Jason D.} and Angela Kirby and Marx, {Christine E.} and McDonald, {Scott D.} and Moore, {Scott D.} and Morey, {Rajendra A.} and Naylor, {Jennifer C.} and Rowland, {Jared A.} and Cindy Swinkels and Szabo, {Steven T.} and Taber, {Katherine H.} and Tupler, {Larry A.} and {Van Voorhees}, {Elizabeth E.} and Yoash-Gantz, {Ruth E.} and Archana Basu and Brick, {Leslie A.} and Shareefa Dalvie and Daskalakis, {Nikolaos P.} and Ensink, {Judith B.M.} and Hemmings, {Sian M.J.} and Ryan Herringa and Sylvanus Ikiyo and Nastassja Koen and Kuan, {Pei Fen} and Janitza Montalvo-Ortiz and Danny Nispeling and John Pfeiffer and Qin, {Xue Jun} and Ressler, {Kerry J.} and Dick Schijven and Soraya Seedat and Gen Shinozaki and Sumner, {Jennifer A.} and Patricia Swart and Audrey Tyrka and {Van Zuiden}, Mirjam and Agaz Wani and Wolf, {Erika J.} and Anthony Zannas and Monica Uddin and Nievergelt, {Caroline M.} and {INTRuST Clinical Consortium} and {VA Mid-Atlantic MIRECC Workgroup} and {PGC PTSD Epigenetics Workgroup}",

year = "2020",

month = dec,

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

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group UK",

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, PF, 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, Marx, C, Grant, G, Stein, M, Qin, XJ, Jain, S, McAllister, TW, Zafonte, R, Lang, A, Coimbra, R, Andaluz, N, Shutter, L, George, MS, Brancu, M, Calhoun, PS, Dedert, E, Elbogen, EB, Fairbank, JA, Hurley, RA, Kilts, JD, Kirby, A, Marx, CE, McDonald, SD, Moore, SD, Morey, RA, Naylor, JC, Rowland, JA, Swinkels, C, Szabo, ST, Taber, KH, Tupler, LA, Van Voorhees, EE, Yoash-Gantz, RE, Basu, A, Brick, LA, Dalvie, S, Daskalakis, NP, Ensink, JBM, Hemmings, SMJ, Herringa, R, Ikiyo, S, Koen, N, Kuan, PF, Montalvo-Ortiz, J, Nispeling, D, Pfeiffer, J, Qin, XJ, Ressler, KJ, Schijven, D, Seedat, S, Shinozaki, G, Sumner, JA, Swart, P, Tyrka, A, Van Zuiden, M, Wani, A, Wolf, EJ, Zannas, A, 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 - Marx, Christine

AU - Grant, Gerry

AU - Stein, Murray

AU - Qin, Xue Jun

AU - Jain, Sonia

AU - McAllister, Thomas W.

AU - Zafonte, Ross

AU - Lang, Ariel

AU - Coimbra, Raul

AU - Andaluz, Norberto

AU - Shutter, Lori

AU - George, Mark S.

AU - Brancu, Mira

AU - Calhoun, Patrick S.

AU - Dedert, Eric

AU - Elbogen, Eric B.

AU - Fairbank, John A.

AU - Hurley, Robin A.

AU - Kilts, Jason D.

AU - Kirby, Angela

AU - Marx, Christine E.

AU - McDonald, Scott D.

AU - Moore, Scott D.

AU - Morey, Rajendra A.

AU - Naylor, Jennifer C.

AU - Rowland, Jared A.

AU - Swinkels, Cindy

AU - Szabo, Steven T.

AU - Taber, Katherine H.

AU - Tupler, Larry A.

AU - Van Voorhees, Elizabeth E.

AU - Yoash-Gantz, Ruth E.

AU - Basu, Archana

AU - Brick, Leslie A.

AU - Dalvie, Shareefa

AU - Daskalakis, Nikolaos P.

AU - Ensink, Judith B.M.

AU - Hemmings, Sian M.J.

AU - Herringa, Ryan

AU - Ikiyo, Sylvanus

AU - Koen, Nastassja

AU - Kuan, Pei Fen

AU - Montalvo-Ortiz, Janitza

AU - Nispeling, Danny

AU - Pfeiffer, John

AU - Qin, Xue Jun

AU - Ressler, Kerry J.

AU - Schijven, Dick

AU - Seedat, Soraya

AU - Shinozaki, Gen

AU - Sumner, Jennifer A.

AU - Swart, Patricia

AU - Tyrka, Audrey

AU - Van Zuiden, Mirjam

AU - Wani, Agaz

AU - Wolf, Erika J.

AU - Zannas, Anthony

AU - Uddin, Monica

AU - Nievergelt, Caroline M.

AU - INTRuST Clinical Consortium

AU - VA Mid-Atlantic MIRECC Workgroup

AU - PGC PTSD Epigenetics Workgroup

PY - 2020/12

Y1 - 2020/12

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85096786381&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-19615-x

DO - 10.1038/s41467-020-19615-x

M3 - Article

C2 - 33235198

AN - SCOPUS:85096786381

VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 5965

ER -

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

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