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Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

ABSTRACT: Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

SUBMITTER: Smith AK

PROVIDER: S-EPMC7686485 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

Smith Alicia K AK Ratanatharathorn Andrew A Maihofer Adam X AX Naviaux Robert K RK Aiello Allison E AE Amstadter Ananda B AB Ashley-Koch Allison E AE Baker Dewleen G DG Beckham Jean C JC Boks Marco P MP Bromet Evelyn E Dennis Michelle M Galea Sandro S Garrett Melanie E ME Geuze Elbert E Guffanti Guia G Hauser Michael A MA Katrinli Seyma S Kilaru Varun V Kessler Ronald C RC Kimbrel Nathan A NA Koenen Karestan C KC Kuan Pei-Fen PF Li Kefeng K Logue Mark W MW Lori Adriana A Luft Benjamin J BJ Miller Mark W MW Naviaux Jane C JC Nugent Nicole R NR Qin Xuejun X Ressler Kerry J KJ Risbrough Victoria B VB Rutten Bart P F BPF Stein Murray B MB Ursano Robert J RJ Vermetten Eric E Vinkers Christiaan H CH Wang Lin L Youssef Nagy A NA Uddin Monica M Nievergelt Caroline M CM

Nature communications 20201124 1

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relativ ...[more]

PMID: 33235198

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Project description:BackgroundEpigenetic 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.ResultsStage 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.ConclusionsThis 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.

Project description:ObjectiveThe purpose of this study was to examine associations between level of kinesiophobia and improvement in physical function during recovery from lower extremity injury.MethodsA total 430 adults (mean [SD]: age = 27.3 [6.4] years; sex = 70.5% men; body mass index = 27.6 [5.2] kg/m2) were included in the analyses. Using the Patient-Reported Outcomes Measurement Information System, physical function was evaluated in parallel with treatment from a physical therapist at the initial visit and every 3 weeks until final visit or up to 6 months. A Tampa Scale of Kinesiophobia (TSK-17) score of >41 indicated elevated TSK. Four TSK groups were identified: (1) TSK score improved from >41 at initial visit to <41 by final visit (TSK_I), (2) TSK score was <41 at initial and final visits (TSK-), (3) TSK score was >41 at initial and final visits (TSK+), and (4) TSK score worsened from <41 at initial visit to ≥41 by final visit (TSK_W). Linear mixed effects models were used to examine differences between groups in improved physical function over time, with adjustment for depression and self-efficacy.ResultsGroups with elevated kinesiophobia at the final visit had smaller positive improvements in physical function (mean change [95% CI]: TSK+ = 7.1 [4.8-9.4]; TSK_W: 6.0 [2.6-9.4]) compared with groups without elevated kinesiophobia at the final visit (TSK_I = 9.8 [6.4-13.3]; TSK- = 9.7 [8.1-11.3]) by 12 weeks.ConclusionsElevated kinesiophobia that persists or develops over the course of care is associated with less improvement in physical function within military and civilian cohorts.ImpactThe findings of this prospective longitudinal study support the need to assess for elevated kinesiophobia throughout the course of care because of its association with decreased improvement in physical function.Lay summaryTo help improve your physical function, your physical therapist can monitor the interaction between fear of movement and your clinical outcomes over the course of treatment.

Dataset Information

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

Publications

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

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