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Author Notes:

Correspondence: loguem@bu.edu

Author contributions: Authors MWL, MWM, EJW, BRH, FGM, AKS, and NPD contributed to study design, data interpretation, and drafting of the manuscript. MWL, ZZ, and YZ analyzed data and/or prepared figures and tables for the manuscript. consortium meta-analysis used for replication.

MU, CMN, AEA-K, DGB, JCB, MEG, MPB, EG, GAG, MAH, RCK, NAK, AXM, CEM, X-JQ, VBR, BPFR, MBS, RJU, EV, CHV, and EBW contributed to the. AS and SAS contributed to the generation of the DNAm data for the TRACTS study. REM, WPM, JPH, and MV supplied samples and phenotype data used in the study. All authors reviewed and approved the manuscript prior to submission.

Disclosures: FM participated in this study while also an NIMH-funded research post-doctoral fellow at Boston University/VA Boston Healthcare System, but is currently an employee of BlackThorn Therapeutics.

MBS has in the past 3 years been a consultant for Actelion, Aptinyx, Bionomics, Dart Neuroscience, Healthcare Management Technologies, Janssen, Neurocrine Biosciences, Oxeia Biopharmaceuticals, Pfizer, and Resilience Therapeutics

In the past 3 years, RCK received support for his epidemiological studies from Sanofi Aventis; was a consultant for DataStat, Inc., Johnson & Johnson Wellness and Prevention, Sage Pharmaceuticals, Shire, Takeda; and served on an advisory board for the Johnson & Johnson Services Inc. Lake Nona Life Project.

None of the remaining authors have any conflicts to disclose. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, the Department of Defense, NIMH, or the US government.

Subjects:

Research Funding:

This work was funded by I01BX003477, a Department of Veterans Affairs BLR&D grant to MWL, 1R03AG051877, 1R21AG061367-01, and 1I01CX001276-01A2 to EJW, 5T32MH019836-18 to FGM, R21MH102834 to MWM, 1R01MH108826 to Smith/Logue/Nievergelt/Uddin, the National Center for PTSD: Behavioral Sciences Division, and the Translational Research Center for TBI and Stress Disorders (TRACTS), a Department of Veterans Affairs Rehabilitation Research and Development (RR&D) Traumatic Brain Injury Center of Excellence (B3001-C) at VA Boston Healthcare System. Genotype and methylation data for the TRACTS and Brain Bank Cohort was generated with the support of resources and of facilities at the Pharmacogenomics Analysis Laboratory (Research Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas),

a core research laboratory funded by the Cooperative Studies Program, Research and Development, Department of Veterans Affairs. Marine Resiliency Study (MRS) funding from The Marine Corps, Navy Bureau of Medicine and Surgery (BUMED) and VA Health Research and Development (HSR&D) who provided funding for MRS data collection and analysis (PI DGB) and NIH R01MH093500 which funded the GWAS assays and analysis (PI CMN). Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 (2009-2015) with the National Institutes of Health, National Institute of Mental Health (NIH/NIMH). Subsequently, STARRS-LS was sponsored and funded by the Department of Defense (USUHS grant no. HU0001-15-2-0004).

Data collection of PRISMO was funded by the Dutch Ministry of Defence, and DNA methylation analyses in PRISMO were funded by the VENI Award fellowship from the Netherlands Organisation for Scientific Research (NWO, grant no. 916.11.086).

The PTSD and TBI Injury and Traumatic Stress Clinical Consortium (INTRuST) was funded by a grant from the US Department of Defense (PI: Stein, MB): W81XWH08-2-0159. Mid-Atlantic Mental Illness Research Education and Clinical Center the study of Post-Deployment Mental Health Study funding included a Clinical Sciences Research and Development (CSR&D) Research Career Scientist Award (#11S-RCS-009) to Dr. Beckham, a CSR&D Career Development Award (#IK2 CX000525) to Dr. Kimbrel, and Biomedical and Laboratory Research and Development (BLR&D) Merit Award to Dr. Beckham from the US Department of Veterans Affairs (VA).

This work was also supported by the VA Mid-Atlantic Mental Illness Research, Education and Clinical Center (MIRECC), the Durham Veterans Affairs Medical Center, the VA Office of Mental Health Services, and the VA Office of Research and Development.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Genetics & Heredity
  • Metabolic syndrome
  • Peripheral syndrome
  • Controlled trial
  • PTSD
  • Gene
  • Expression
  • Smoking
  • Exposure
  • Cortex
  • Age

An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci

Tools:

Journal Title:

Clinical Epigenetics

Volume:

Volume 12, Number 1

Publisher:

, Pages 46-46

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). Methods: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). Results: The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10-7, p adj = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10-6), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10-5, p adj = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10-6, p adj = 0.042). Conclusions: The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.

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© 2022 BioMed Central Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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