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Longitudinal epigenetic variation of DNA methyltransferase genes is associated with vulnerability to post-traumatic stress disorder

Published online by Cambridge University Press:  25 April 2014

L. Sipahi ,
D. E. Wildman ,
A. E. Aiello ,
K. C. Koenen ,
S. Galea ,
A. Abbas  and
M. Uddin
L. Sipahi
Affiliation:
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
D. E. Wildman
Affiliation:
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
A. E. Aiello
Affiliation:
Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA
K. C. Koenen
Affiliation:
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
S. Galea
Affiliation:
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
A. Abbas
Affiliation:
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
M. Uddin*
Affiliation:
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA
*
* Address for correspondence: M. Uddin, Ph.D., Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 3309 Scott Hall, 540 E. Canfield Avenue, Detroit, MI 48201, USA. (Email: [email protected])
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Abstract

Background.

Epigenetic differences exist between trauma-exposed individuals with and without post-traumatic stress disorder (PTSD). It is unclear whether these epigenetic differences pre-exist, or arise following, trauma and PTSD onset.

Method.

In pre- and post-trauma samples from a subset of Detroit Neighborhood Health Study participants, DNA methylation (DNAm) was measured at DNA methyltransferase 1 (DNMT1), DNMT3A, DNMT3B and DNMT3L. Pre-trauma DNAm differences and changes in DNAm from pre- to post-trauma were assessed between and within PTSD cases (n = 30) and age-, gender- and trauma exposure-matched controls (n = 30). Pre-trauma DNAm was tested for association with post-trauma symptom severity (PTSS) change. Potential functional consequences of DNAm differences were explored via bioinformatic search for putative transcription factor binding sites (TFBS).

Results.

DNMT1 DNAm increased following trauma in PTSD cases (p = 0.001), but not controls (p = 0.067). DNMT3A and DNMT3B DNAm increased following trauma in both cases (DNMT3A: p = 0.009; DNMT3B: p < 0.001) and controls (DNMT3A: p = 0.002; DNMT3B: p < 0.001). In cases only, pre-trauma DNAm was lower at a DNMT3B CpG site that overlaps with a TFBS involved in epigenetic regulation (p = 0.001); lower pre-trauma DNMT3B DNAm at this site was predictive of worsening of PTSS post-trauma (p = 0.034). Some effects were attenuated following correction for multiple hypothesis testing.

Conclusions.

DNAm among trauma-exposed individuals shows both longitudinal changes and pre-existing epigenetic states that differentiate individuals who are resilient versus susceptible to PTSD. These distinctive DNAm differences within DNMT loci may contribute to genome-wide epigenetic profiles of PTSD.

Keywords

DNA methylationepidemiologyepigeneticslongitudinal studiespost-traumatic stress disorder
Type
Original Articles
Information
Psychological Medicine , Volume 44 , Issue 15 , November 2014 , pp. 3165 - 3179
Copyright
Copyright © Cambridge University Press 2014 

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