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Successful treatment of post-traumatic stress disorder reverses DNA methylation marks

Abstract

Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the development of post-traumatic stress disorder (PTSD). However, it is unknown whether successful treatment of PTSD restores these epigenetic marks. This study investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for PTSD in soldiers that obtained remission (N = 21), non-remitted PTSD patients (N = 23), and trauma-exposed military controls (N = 23). In an independent prospective cohort, we then examined whether these DMRs were also relevant for the development of deployment-related PTSD (N = 85). Successful treatment of PTSD was accompanied by significant changes in DNA methylation at 12 differentially methylated regions (DMRs) in the genes: APOB, MUC4, EDN2, ZFP57, GPX6, CFAP45, AFF3, TP73, UBCLP1, RPL13P, and two intergenic regions (p values < 0.0001 were confirmed using permutation and sensitivity analyses). Of the 12 DMRs related to PTSD symptom reduction, consistent prospective evidence was found for ZFP57 methylation changes related to changing PTSD symptoms (B = −0.84, t = −2.49, p = 0.014). Increasing ZFP57 methylation related to PTSD symptom reduction was present over and above the relation with symptoms, suggesting that psychological treatments exert biological effects independent of symptom reduction. Together, these data provide longitudinal evidence that ZFP57 methylation is involved in both the development and successful treatment of deployment-related PTSD. This study is a first step to disentangle the interaction between psychological and biological systems to identify genomic regions relevant for the etiology and treatment of stress-related disorders such as PTSD.

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References

  1. Daskalakis NP, Rijal CM, King C, Huckins LM, Ressler KJ. Recent genetics and epigenetics approaches to PTSD. Curr. Psychiatry Rep. 2018;20:30.

    Article  Google Scholar 

  2. Zannas AS, Provencal N, Binder EB. Epigenetics of Posttraumatic Stress Disorder: Current evidence, challenges, and future directions. Biol Psychiatry. 2015;78:327–35.

    CAS  Article  Google Scholar 

  3. Rutten BPF, Vermetten E, Vinkers CH, Ursini G, Daskalakis NP, Pishva E, et al. Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder. Mol Psychiatry. 2018;23:1145–56.

    CAS  Article  Google Scholar 

  4. Yehuda R, Daskalakis NP, Desarnaud F, Makotkine I, Lehrner AL, Koch E, et al. Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Front Psychiatry. 2013;4:118.

    Article  Google Scholar 

  5. Seidler GH, Wagner FE. Comparing the efficacy of EMDR and trauma-focused cognitive-behavioral therapy in the treatment of PTSD: a meta-analytic study. Psychol Med. 2006;36:1515–22.

    Article  Google Scholar 

  6. Bradley R, Greene J, Russ E, Dutra L, Westen D. A multidimensional meta-analysis of psychotherapy for PTSD. Am J Psychiatry. 2005;162:214–27.

    Article  Google Scholar 

  7. Fonzo GA, Simmons AN, Thorp SR, Norman SB, Paulus MP, Stein MB. Exaggerated and disconnected insular-amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorder. Biol Psychiatry. 2010;68:433–41.

    Article  Google Scholar 

  8. Brown VM, Morey RA. Neural systems for cognitive and emotional processing in posttraumatic stress disorder. Front Psychol. 2012;3:449.

    PubMed  PubMed Central  Google Scholar 

  9. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, et al. The development of a Clinician-Administered PTSD Scale. J Trauma Stress. 1995;8:75–90.

    CAS  Article  Google Scholar 

  10. Weathers FW, Keane TM, Davidson JR. Clinician-administered PTSD scale: a review of the first ten years of research. Depress Anxiety. 2001;13:132–56.

    CAS  Article  Google Scholar 

  11. Watson D, Clark LA, Weber K, Assenheimer JS, Strauss ME, McCormick RA. Testing a tripartite model: II. Exploring the symptom structure of anxiety and depression in student, adult, and patient samples. J Abnorm Psychol. 1995;104:15–25.

    CAS  Article  Google Scholar 

  12. de Beurs E, den Hollander-Gijsman ME, Helmich S, Zitman FG. The tripartite model for assessing symptoms of anxiety and depression: psychometrics of the Dutch version of the mood and anxiety symptoms questionnaire. Behav Res Ther. 2007;45:1609–17.

    Article  Google Scholar 

  13. Weathers FW, Ruscio AM, Keane TM. Psychometric properties of nine scoring rules for the Clinician-Administered Posttraumatic Stress Disorder Scale. Psychol Assess. 1999;11:124–33.

    Article  Google Scholar 

  14. Eekhout I, Reijnen A, Vermetten E, Geuze E. Post-traumatic stress symptoms 5 years after military deployment to Afghanistan: an observational cohort study. Lancet Psychiat. 2016;3:58–64.

    Article  Google Scholar 

  15. Min JL, Hemani G, Davey Smith G, Relton C, Suderman M. Meffil: efficient normalization and analysis of very large DNA methylation datasets. Bioinformatics. 2018;34:3983–9.

    CAS  Article  Google Scholar 

  16. Fortin JP, Labbe A, Lemire M, Zanke BW, Hudson TJ, Fertig EJ, et al. Functional normalization of 450k methylation array data improves replication in large cancer studies. Genome Biol. 2014;15:503.

    Article  Google Scholar 

  17. Chen YA, Lemire M, Choufani S, Butcher DT, Grafodatskaya D, Zanke BW, et al. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation microarray. Epigenetics. 2013;8:203–9.

    CAS  Article  Google Scholar 

  18. Du P, Zhang X, Huang CC, Jafari N, Kibbe WA, Hou L, et al. Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC bioinformatics. 2010;11:587.

    CAS  Article  Google Scholar 

  19. Teschendorff AE, Zhuang J, Widschwendter M. Independent surrogate variable analysis to deconvolve confounding factors in large-scale microarray profiling studies. Bioinformatics. 2011;27:1496–505.

    CAS  Article  Google Scholar 

  20. Koestler DC, Christensen B, Karagas MR, Marsit CJ, Langevin SM, Kelsey KT, et al. Blood-based profiles of DNA methylation predict the underlying distribution of cell types: a validation analysis. Epigenetics. 2013;8:816–26.

    CAS  Article  Google Scholar 

  21. Peters TJ, Buckley MJ, Statham AL, Pidsley R, Samaras K, VL R, et al. De novo identification of differentially methylated regions in the human genome. Epigene chromatin. 2015;8:6.

    Article  Google Scholar 

  22. Jakobsson J, Cordero MI, Bisaz R, Groner AC, Busskamp V, Bensadoun JC, et al. KAP1-mediated epigenetic repression in the forebrain modulates behavioral vulnerability to stress. Neuron. 2008;60:818–31.

    CAS  Article  Google Scholar 

  23. Thomas M, Knoblich N, Wallisch A, Glowacz K, Becker-Sadzio J, Gundel F, et al. Increased BDNF methylation in saliva, but not blood, of patients with borderline personality disorder. Clin Epigenetics. 2018;10:109.

    Article  Google Scholar 

  24. Ziegler C, Richter J, Mahr M, Gajewska A, Schiele MA, Gehrmann A, et al. MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy. Trans Psychiatry. 2016;6:e773.

    CAS  Article  Google Scholar 

  25. Knoblich N, Gundel F, Bruckmann C, Becker-Sadzio J, Frischholz C, Nieratschker V. DNA methylation of APBA3 and MCF2 in borderline personality disorder: Potential biomarkers for response to psychotherapy. Eur Neuropsychopharmacol. 2018;28:252–63.

    CAS  Article  Google Scholar 

  26. Hannon E, Knox O, Sugden K, Burrage J, Wong CCY, Belsky DW, et al. Characterizing genetic and environmental influences on variable DNA methylation using monozygotic and dizygotic twins. PLoS Genet. 2018;14:e1007544.

    Article  Google Scholar 

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Acknowledgements

MB and EG had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. MB and DN conducted the analyses.

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Correspondence to Christiaan H. Vinkers or Marco P. Boks.

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Vinkers, C.H., Geuze, E., van Rooij, S.J.H. et al. Successful treatment of post-traumatic stress disorder reverses DNA methylation marks. Mol Psychiatry 26, 1264–1271 (2021). https://doi.org/10.1038/s41380-019-0549-3

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