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

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, padj?=?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, padj?=?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, padj?=?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.

SUBMITTER: Logue MW

PROVIDER: S-EPMC7071645 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Logue Mark W MW Miller Mark W MW Wolf Erika J EJ Huber Bertrand Russ BR Morrison Filomene G FG Zhou Zhenwei Z Zheng Yuanchao Y Smith Alicia K AK Daskalakis Nikolaos P NP Ratanatharathorn Andrew A Uddin Monica M Nievergelt Caroline M CM Ashley-Koch Allison E AE Baker Dewleen G DG Beckham Jean C JC Garrett Melanie E ME Boks Marco P MP Geuze Elbert E Grant Gerald A GA Hauser Michael A MA Kessler Ronald C RC Kimbrel Nathan A NA Maihofer Adam X AX Marx Christine E CE Qin Xue-Jun XJ Risbrough Victoria B VB Rutten Bart P F BPF Stein Murray B MB Ursano Robert J RJ Vermetten Eric E Vinkers Christiaan H CH Ware Erin B EB Stone Annjanette A Schichman Steven A SA McGlinchey Regina E RE Milberg William P WP Hayes Jasmeet P JP Verfaellie Mieke M

Clinical epigenetics 20200314 1

<h4>Background</h4>Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD).<h4>Methods</h4>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 ...[more]

PMID: 32171335

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Project description:ImportancePosttraumatic stress disorder (PTSD) symptom reduction is linked with lower risk of incident type 2 diabetes (T2D), but little is known about the association between PTSD and comorbid T2D outcomes. Whether PTSD is a modifiable risk factor for adverse T2D outcomes is unknown.ObjectiveTo determine whether patients with PTSD who improved and no longer met diagnostic criteria for PTSD had a lower risk of adverse T2D outcomes compared with patients with persistent PTSD.Design, setting, and participantsThis retrospective cohort study used deidentified data from US Veterans Health Administration (VHA) historical medical records (from October 1, 2011, to September 30, 2022) to create a cohort of patients aged 18 to 80 years with comorbid PTSD and T2D. Data analysis was performed from March 1 to June 1, 2024.ExposuresDiagnoses of PTSD and T2D.Main outcomes and measuresThe main outcomes were insulin initiation, poor glycemic control, any microvascular complication, and all-cause mortality. Improvement of PTSD was defined as no longer meeting PTSD diagnostic criteria, per a PTSD Checklist score of less than 33. Entropy balancing controlled for confounding. Survival and competing risk models estimated the association between meeting PTSD criteria and T2D outcomes. Subgroup analyses examined variation by age, sex, race, PTSD severity, and comorbid depression status.ResultsThe study cohort included 10 002 veterans. More than half of patients (65.3%) were aged older than 50 years and most (87.2%) were men. Patients identified as Black (31.6%), White (62.7%), or other race (5.7%). Before controlling for confounding with entropy balancing, patients who no longer met PTSD diagnostic criteria had similar incidence rates for starting insulin (22.4 vs 24.4 per 1000 person-years), poor glycemic control (137.1 vs 133.7 per 1000 person-years), any microvascular complication (108.4 vs 104.8 per 1000 person-years), and all-cause mortality (11.2 vs 11.0 per 1000 person-years) compared with patients with persistent PTSD. After controlling for confounding, no longer meeting PTSD criteria was associated with a lower risk of microvascular complications (hazard ratio [HR], 0.92 [95% CI, 0.85-0.99]). Among veterans aged 18 to 49 years, no longer meeting PTSD criteria was associated with a lower risk of insulin initiation (HR, 0.69 [95% CI, 0.53-0.88]) and all-cause mortality (HR, 0.39 [95% CI, 0.19-0.83]). Among patients without depression, no longer meeting PTSD criteria was associated with a lower risk of insulin initiation (HR, 0.73 [95% CI, 0.55-0.97]).Conclusions and relevanceThe findings of this cohort study of patients with comorbid PTSD and T2D suggest that PTSD is a modifiable risk factor associated with a modest reduction in microvascular complications. Further research is needed to determine whether findings are similar in non-VHA health care settings.

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

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

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