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

31 Citations (Web of Science)

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

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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.",

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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}",

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

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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

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

VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 5965

ER -