PMID- 31931860 OWN - NLM STAT- MEDLINE DCOM- 20210602 LR - 20240327 IS - 1868-7083 (Electronic) IS - 1868-7075 (Print) IS - 1868-7075 (Linking) VI - 12 IP - 1 DP - 2020 Jan 13 TI - Longitudinal epigenome-wide association studies of three male military cohorts reveal multiple CpG sites associated with post-traumatic stress disorder. PG - 11 LID - 10.1186/s13148-019-0798-7 [doi] LID - 11 AB - 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 x 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. FAU - Snijders, Clara AU - Snijders C AD - Department of Psychiatry and Neuropsychology, School for Mental health and Neuroscience, Maastricht University, Maastricht, Limburg, Netherlands. FAU - Maihofer, Adam X AU - Maihofer AX AD - Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. AD - Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. AD - Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. FAU - Ratanatharathorn, Andrew AU - Ratanatharathorn A AD - Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. FAU - Baker, Dewleen G AU - Baker DG AD - Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. AD - Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. AD - Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. FAU - Boks, Marco P AU - Boks MP AD - Department of Psychiatry, UMC Utrecht Brain Center, Utrecht, Utrecht, Netherlands. FAU - Geuze, Elbert AU - Geuze E AD - Department of Psychiatry, UMC Utrecht Brain Center, Utrecht, Utrecht, Netherlands. AD - Brain Research & Innovation Centre, Netherlands Ministry of Defense, Utrecht, Utrecht, Netherlands. FAU - Jain, Sonia AU - Jain S AD - Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA. FAU - Kessler, Ronald C AU - Kessler RC AD - Department of Health Care Policy, Harvard Medical School, Boston, MA, USA. FAU - Pishva, Ehsan AU - Pishva E AD - Department of Psychiatry and Neuropsychology, School for Mental health and Neuroscience, Maastricht University, Maastricht, Limburg, Netherlands. AD - College of Medicine and Health, University of Exeter Medical School, Exeter, UK. FAU - Risbrough, Victoria B AU - Risbrough VB AD - Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. AD - Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. AD - Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. FAU - Stein, Murray B AU - Stein MB AD - Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. AD - Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. AD - Million Veteran Program, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. FAU - Ursano, Robert J AU - Ursano RJ AD - Department of Psychiatry, Uniformed Services University, Bethesda, MD, USA. FAU - Vermetten, Eric AU - Vermetten E AD - Arq, Psychotrauma Research Expert Group, Diemen, North Holland, Netherlands. AD - Department of Psychiatry, Leiden University Medical Center, Leiden, South Holland, Netherlands. AD - Military Mental Healthcare, Netherlands Ministry of Defense, Utrecht, Utrecht, Netherlands. AD - Department of Psychiatry, New York University School of Medicine, New York, NY, USA. FAU - Vinkers, Christiaan H AU - Vinkers CH AD - Department of Anatomy and Neurosciences, Amsterdam UMC (location VUmc), Amsterdam, Holland, Netherlands. AD - Department of Psychiatry, Amsterdam UMC (location VUmc), Amsterdam, Holland, Netherlands. CN - PGC PTSD EWAS Consortium FAU - Smith, Alicia K AU - Smith AK AD - Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA. AD - Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA. FAU - Uddin, Monica AU - Uddin M AD - Genomics Program, University of South Florida College of Public Health, Tampa, FL, USA. FAU - Rutten, Bart P F AU - Rutten BPF AD - Department of Psychiatry and Neuropsychology, School for Mental health and Neuroscience, Maastricht University, Maastricht, Limburg, Netherlands. FAU - Nievergelt, Caroline M AU - Nievergelt CM AUID- ORCID: 0000-0001-5766-8923 AD - Department of Psychiatry and Neuropsychology, School for Mental health and Neuroscience, Maastricht University, Maastricht, Limburg, Netherlands. cnievergelt@ucsd.edu. AD - Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. cnievergelt@ucsd.edu. AD - Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. cnievergelt@ucsd.edu. AD - Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. cnievergelt@ucsd.edu. LA - eng GR - R01 MH093500/MH/NIMH NIH HHS/United States GR - R01 MH124847/MH/NIMH NIH HHS/United States GR - R01 MH106595/MH/NIMH NIH HHS/United States GR - R01 MH108826/MH/NIMH NIH HHS/United States GR - U01 MH087981/MH/NIMH NIH HHS/United States PT - Journal Article PT - Meta-Analysis PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20200113 PL - Germany TA - Clin Epigenetics JT - Clinical epigenetics JID - 101516977 RN - 0 (Cell Cycle Proteins) RN - 0 (MAD1L1 protein, human) SB - IM MH - Adult MH - Case-Control Studies MH - Cell Cycle Proteins/genetics MH - Cohort Studies MH - CpG Islands/*genetics MH - DNA Methylation/genetics MH - Epigenesis, Genetic/*genetics MH - Epigenome/genetics MH - Genomics/methods MH - Humans MH - Longitudinal Studies MH - Male MH - Military Personnel/*psychology MH - Polymorphism, Single Nucleotide/genetics MH - Stress Disorders, Post-Traumatic/ethnology/*genetics PMC - PMC6958602 OTO - NOTNLM OT - DNA methylation OT - EWAS OT - Epigenetics OT - Longitudinal OT - Meta-analysis OT - PTSD OT - Trauma COIS- RCK received support for his epidemiological studies from Sanofi Aventis; was a consultant for 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. Kessler is a co-owner of DataStat, Inc., a market research firm that carries out healthcare research. 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. The other authors declare that they have no competing interests. EDAT- 2020/01/15 06:00 MHDA- 2021/06/03 06:00 PMCR- 2020/01/13 CRDT- 2020/01/15 06:00 PHST- 2019/09/24 00:00 [received] PHST- 2019/12/19 00:00 [accepted] PHST- 2020/01/15 06:00 [entrez] PHST- 2020/01/15 06:00 [pubmed] PHST- 2021/06/03 06:00 [medline] PHST- 2020/01/13 00:00 [pmc-release] AID - 10.1186/s13148-019-0798-7 [pii] AID - 798 [pii] AID - 10.1186/s13148-019-0798-7 [doi] PST - epublish SO - Clin Epigenetics. 2020 Jan 13;12(1):11. doi: 10.1186/s13148-019-0798-7.