Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD

Alicia K Smith; Seyma Katrinli; Adam X Maihofer; Allison E Aiello; Dewleen G Baker; Marco P Boks; Leslie A Brick; Chia-Yen Chen; Shareefa Dalvie; Negar Fani; Catherine B Fortier; Joel Gelernter; Elbert Geuze; Charles F Gillespie; Jasmeet P Hayes; Suzi Hong; Ronald C Kessler; Anthony P King; Nastassja Koen; Karestan C Koenen; Israel Liberzon; Sarah D Linnstaedt; Samuel A McLean; Vasiliki Michopoulos; William P Milberg; Mark W Miller; Mary S Mufford; Nicole R Nugent; Holly K Orcutt; Abigail Powers; Sheila A M Rauch; Kerry J Ressler; Victoria B Risbrough; Bart P F Rutten; Jordan W Smoller; Dan J Stein; Murray B Stein; Robert J Ursano; Mieke H Verfaellie; Eric Vermetten; Christiaan H Vinkers; Agaz H Wani; Erin B WareVinkers; Derek E Wildman; Erika J Wolf; Ying Zhao; Mark W Logue; Caroline M Nievergelt; Monica Uddin; Anthony S Zannas

doi:10.1016/j.bbi.2025.04.031

Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD

Alicia K Smith^*, Seyma Katrinli, Adam X Maihofer, Allison E Aiello, Dewleen G Baker, Marco P Boks, Leslie A Brick, Chia-Yen Chen, Shareefa Dalvie, Negar Fani, Catherine B Fortier, Joel Gelernter, Elbert Geuze, Charles F Gillespie, Jasmeet P Hayes, Suzi Hong, Ronald C Kessler, Anthony P King, Nastassja Koen, Karestan C KoenenIsrael Liberzon, Sarah D Linnstaedt, Samuel A McLean, Vasiliki Michopoulos, William P Milberg, Mark W Miller, Mary S Mufford, Nicole R Nugent, Holly K Orcutt, Abigail Powers, Sheila A M Rauch, Kerry J Ressler, Victoria B Risbrough, Bart P F Rutten, Jordan W Smoller, Dan J Stein, Murray B Stein, Robert J Ursano, Mieke H Verfaellie, Eric Vermetten, Christiaan H Vinkers, Agaz H Wani, Erin B WareVinkers, Derek E Wildman, Erika J Wolf, Ying Zhao, Mark W Logue, Caroline M Nievergelt, Monica Uddin, Anthony S Zannas,

^*Corresponding author for this work

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

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Abstract

Background: Epigenetic modifications, including DNA methylation (DNAm), can change in response to traumatic stress exposure, and may help to distinguish between individuals with and without PTSD. Here, we examine the DNAm patterns specific to immune cell types and inflammation in those with PTSD. Methods: This study includes 3,277 participants from 11 cohorts participating in the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. DNAm was assayed from blood with the MethylationEPIC BeadChip. A standardized QC pipeline was applied and used to impute cell composition. Within each cohort, we identified cell-type-specific DNAm patterns associated with PTSD, controlling for sex (if applicable), age, and ancestry. Meta-analyses were performed from summary statistics. Results: PTSD cases had lower proportions of B cells and NK cells as well as higher proportions of neutrophils when compared to trauma-exposed controls. Overall, we identified 96 PTSD-associated CpGs across six types of immune cells. Most of these differences were identified in B cells, with 95 % exhibiting lower methylation levels in those with PTSD. Interestingly, the PTSD-associated CpGs annotated to a gene in B cells were enriched in a recent GWAS of PTSD (p < 0.0001). Conclusions: This study identifies novel PTSD-associated CpGs in individual immune cell types and supports the role of immune dysregulation and inflammation in PTSD.

Original language	English
Pages (from-to)	540-548
Number of pages	9
Journal	Brain, Behavior, and Immunity
Volume	128
Early online date	24 Apr 2025
DOIs	https://doi.org/10.1016/j.bbi.2025.04.031
Publication status	E-pub ahead of print - 24 Apr 2025

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1-s2.0-S0889159125001680-mainFinal published version, 3.18 MBLicence: CC BY

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Smith, A. K., Katrinli, S., Maihofer, A. X., Aiello, A. E., Baker, D. G., Boks, M. P., Brick, L. A., Chen, C.-Y., Dalvie, S., Fani, N., Fortier, C. B., Gelernter, J., Geuze, E., Gillespie, C. F., Hayes, J. P., Hong, S., Kessler, R. C., King, A. P., Koen, N. (2025). Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD. Brain, Behavior, and Immunity, 128, 540-548. Advance online publication. https://doi.org/10.1016/j.bbi.2025.04.031

@article{2bbdbf2a65534f138db9fcbb8a419c3f,

title = "Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD",

abstract = "Background: Epigenetic modifications, including DNA methylation (DNAm), can change in response to traumatic stress exposure, and may help to distinguish between individuals with and without PTSD. Here, we examine the DNAm patterns specific to immune cell types and inflammation in those with PTSD. Methods: This study includes 3,277 participants from 11 cohorts participating in the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. DNAm was assayed from blood with the MethylationEPIC BeadChip. A standardized QC pipeline was applied and used to impute cell composition. Within each cohort, we identified cell-type-specific DNAm patterns associated with PTSD, controlling for sex (if applicable), age, and ancestry. Meta-analyses were performed from summary statistics. Results: PTSD cases had lower proportions of B cells and NK cells as well as higher proportions of neutrophils when compared to trauma-exposed controls. Overall, we identified 96 PTSD-associated CpGs across six types of immune cells. Most of these differences were identified in B cells, with 95 % exhibiting lower methylation levels in those with PTSD. Interestingly, the PTSD-associated CpGs annotated to a gene in B cells were enriched in a recent GWAS of PTSD (p < 0.0001). Conclusions: This study identifies novel PTSD-associated CpGs in individual immune cell types and supports the role of immune dysregulation and inflammation in PTSD.",

author = "Smith, {Alicia K} and Seyma Katrinli and Maihofer, {Adam X} and Aiello, {Allison E} and Baker, {Dewleen G} and Boks, {Marco P} and Brick, {Leslie A} and Chia-Yen Chen and Shareefa Dalvie and Negar Fani and Fortier, {Catherine B} and Joel Gelernter and Elbert Geuze and Gillespie, {Charles F} and Hayes, {Jasmeet P} and Suzi Hong and Kessler, {Ronald C} and King, {Anthony P} and Nastassja Koen and Koenen, {Karestan C} and Israel Liberzon and Linnstaedt, {Sarah D} and McLean, {Samuel A} and Vasiliki Michopoulos and Milberg, {William P} and Miller, {Mark W} and Mufford, {Mary S} and Nugent, {Nicole R} and Orcutt, {Holly K} and Abigail Powers and Rauch, {Sheila A M} and Ressler, {Kerry J} and Risbrough, {Victoria B} and Rutten, {Bart P F} and Smoller, {Jordan W} and Stein, {Dan J} and Stein, {Murray B} and Ursano, {Robert J} and Verfaellie, {Mieke H} and Eric Vermetten and Vinkers, {Christiaan H} and Wani, {Agaz H} and WareVinkers, {Erin B} and Wildman, {Derek E} and Wolf, {Erika J} and Ying Zhao and Logue, {Mark W} and Nievergelt, {Caroline M} and Monica Uddin and Zannas, {Anthony S}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = apr,

day = "24",

doi = "10.1016/j.bbi.2025.04.031",

language = "English",

volume = "128",

pages = "540--548",

journal = "Brain, Behavior, and Immunity",

issn = "0889-1591",

publisher = "Academic Press Inc.",

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Smith, AK, Katrinli, S, Maihofer, AX, Aiello, AE, Baker, DG, Boks, MP, Brick, LA, Chen, C-Y, Dalvie, S, Fani, N, Fortier, CB, Gelernter, J, Geuze, E, Gillespie, CF, Hayes, JP, Hong, S, Kessler, RC, King, AP, Koen, N, Koenen, KC, Liberzon, I, Linnstaedt, SD, McLean, SA, Michopoulos, V, Milberg, WP, Miller, MW, Mufford, MS, Nugent, NR, Orcutt, HK, Powers, A, Rauch, SAM, Ressler, KJ, Risbrough, VB, Rutten, BPF, Smoller, JW, Stein, DJ, Stein, MB, Ursano, RJ, Verfaellie, MH, Vermetten, E, Vinkers, CH, Wani, AH, WareVinkers, EB, Wildman, DE, Wolf, EJ, Zhao, Y, Logue, MW, Nievergelt, CM, Uddin, M, Zannas, AS 2025, 'Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD', Brain, Behavior, and Immunity, vol. 128, pp. 540-548. https://doi.org/10.1016/j.bbi.2025.04.031

TY - JOUR

T1 - Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD

AU - Smith, Alicia K

AU - Katrinli, Seyma

AU - Maihofer, Adam X

AU - Aiello, Allison E

AU - Baker, Dewleen G

AU - Boks, Marco P

AU - Brick, Leslie A

AU - Chen, Chia-Yen

AU - Dalvie, Shareefa

AU - Fani, Negar

AU - Fortier, Catherine B

AU - Gelernter, Joel

AU - Geuze, Elbert

AU - Gillespie, Charles F

AU - Hayes, Jasmeet P

AU - Hong, Suzi

AU - Kessler, Ronald C

AU - King, Anthony P

AU - Koen, Nastassja

AU - Koenen, Karestan C

AU - Liberzon, Israel

AU - Linnstaedt, Sarah D

AU - McLean, Samuel A

AU - Michopoulos, Vasiliki

AU - Milberg, William P

AU - Miller, Mark W

AU - Mufford, Mary S

AU - Nugent, Nicole R

AU - Orcutt, Holly K

AU - Powers, Abigail

AU - Rauch, Sheila A M

AU - Ressler, Kerry J

AU - Risbrough, Victoria B

AU - Rutten, Bart P F

AU - Smoller, Jordan W

AU - Stein, Dan J

AU - Stein, Murray B

AU - Ursano, Robert J

AU - Verfaellie, Mieke H

AU - Vermetten, Eric

AU - Vinkers, Christiaan H

AU - Wani, Agaz H

AU - WareVinkers, Erin B

AU - Wildman, Derek E

AU - Wolf, Erika J

AU - Zhao, Ying

AU - Logue, Mark W

AU - Nievergelt, Caroline M

AU - Uddin, Monica

AU - Zannas, Anthony S

PY - 2025/4/24

Y1 - 2025/4/24

N2 - Background: Epigenetic modifications, including DNA methylation (DNAm), can change in response to traumatic stress exposure, and may help to distinguish between individuals with and without PTSD. Here, we examine the DNAm patterns specific to immune cell types and inflammation in those with PTSD. Methods: This study includes 3,277 participants from 11 cohorts participating in the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. DNAm was assayed from blood with the MethylationEPIC BeadChip. A standardized QC pipeline was applied and used to impute cell composition. Within each cohort, we identified cell-type-specific DNAm patterns associated with PTSD, controlling for sex (if applicable), age, and ancestry. Meta-analyses were performed from summary statistics. Results: PTSD cases had lower proportions of B cells and NK cells as well as higher proportions of neutrophils when compared to trauma-exposed controls. Overall, we identified 96 PTSD-associated CpGs across six types of immune cells. Most of these differences were identified in B cells, with 95 % exhibiting lower methylation levels in those with PTSD. Interestingly, the PTSD-associated CpGs annotated to a gene in B cells were enriched in a recent GWAS of PTSD (p < 0.0001). Conclusions: This study identifies novel PTSD-associated CpGs in individual immune cell types and supports the role of immune dysregulation and inflammation in PTSD.

AB - Background: Epigenetic modifications, including DNA methylation (DNAm), can change in response to traumatic stress exposure, and may help to distinguish between individuals with and without PTSD. Here, we examine the DNAm patterns specific to immune cell types and inflammation in those with PTSD. Methods: This study includes 3,277 participants from 11 cohorts participating in the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. DNAm was assayed from blood with the MethylationEPIC BeadChip. A standardized QC pipeline was applied and used to impute cell composition. Within each cohort, we identified cell-type-specific DNAm patterns associated with PTSD, controlling for sex (if applicable), age, and ancestry. Meta-analyses were performed from summary statistics. Results: PTSD cases had lower proportions of B cells and NK cells as well as higher proportions of neutrophils when compared to trauma-exposed controls. Overall, we identified 96 PTSD-associated CpGs across six types of immune cells. Most of these differences were identified in B cells, with 95 % exhibiting lower methylation levels in those with PTSD. Interestingly, the PTSD-associated CpGs annotated to a gene in B cells were enriched in a recent GWAS of PTSD (p < 0.0001). Conclusions: This study identifies novel PTSD-associated CpGs in individual immune cell types and supports the role of immune dysregulation and inflammation in PTSD.

U2 - 10.1016/j.bbi.2025.04.031

DO - 10.1016/j.bbi.2025.04.031

M3 - Article

C2 - 40286993

SN - 0889-1591

VL - 128

SP - 540

EP - 548

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

ER -

Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD

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