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Clin Epigenetics. 2020 Jan 13;12(1):11. doi: 10.1186/s13148-019-0798-7.

Longitudinal epigenome-wide association studies of three male military cohorts reveal multiple CpG sites associated with post-traumatic stress disorder.

Author information

1
Department of Psychiatry and Neuropsychology, School for Mental health and Neuroscience, Maastricht University, Maastricht, Limburg, Netherlands.
2
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
3
Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
4
Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
5
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
6
Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
7
Department of Psychiatry, UMC Utrecht Brain Center, Utrecht, Utrecht, Netherlands.
8
Brain Research & Innovation Centre, Netherlands Ministry of Defense, Utrecht, Utrecht, Netherlands.
9
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
10
Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
11
College of Medicine and Health, University of Exeter Medical School, Exeter, UK.
12
Million Veteran Program, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
13
Department of Psychiatry, Uniformed Services University, Bethesda, MD, USA.
14
Arq, Psychotrauma Research Expert Group, Diemen, North Holland, Netherlands.
15
Department of Psychiatry, Leiden University Medical Center, Leiden, South Holland, Netherlands.
16
Military Mental Healthcare, Netherlands Ministry of Defense, Utrecht, Utrecht, Netherlands.
17
Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
18
Department of Anatomy and Neurosciences, Amsterdam UMC (location VUmc), Amsterdam, Holland, Netherlands.
19
Department of Psychiatry, Amsterdam UMC (location VUmc), Amsterdam, Holland, Netherlands.
20
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
21
Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA.
22
Genomics Program, University of South Florida College of Public Health, Tampa, FL, USA.
23
Department of Psychiatry and Neuropsychology, School for Mental health and Neuroscience, Maastricht University, Maastricht, Limburg, Netherlands. cnievergelt@ucsd.edu.
24
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. cnievergelt@ucsd.edu.
25
Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. cnievergelt@ucsd.edu.
26
Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. cnievergelt@ucsd.edu.

Abstract

BACKGROUND:

Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis.

RESULTS:

Stage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10-08) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region.

CONCLUSIONS:

This study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD.

KEYWORDS:

DNA methylation; EWAS; Epigenetics; Longitudinal; Meta-analysis; PTSD; Trauma

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