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

Logue, Mark W.; Miller, Mark W.; Wolf, Erika J.; Huber, Bertrand R.; Morrison, Filomene G.; Zhou, Zhenwei; Zheng, Yuanchao; Smith, Alicia K.; Daskalakis, Nikolaos P.; Ratanatharathorn, Andrew; Uddin, Monica; Nievergelt, Caroline M.; Ashley–Koch, Allison; Baker, Dewleen G.; Beckham, Jean C.; Garrett, Melanie E.; Boks, Marco P.; Geuze, Elbert; Grant, Gerald A.; Hauser, Michael A.; Kessler, Ronald C.; Kimbrel, Nathan A.; Maihofer, Adam X.; Marx, Christine E.; Qin, Xuejun; Risbrough, Victoria B.; Rutten, Bart P. F.; Stein, Murray B.; Ursano, Robert J.; Vermetten, Eric; Vinkers, Christiaan H.; Ware, Erin B.; Stone, Annjanette; Schichman, Steven A.; McGlinchey, Regina E.; Milberg, William; Hayes, Jasmeet P.; Verfaellie, Mieke

doi:10.1186/s13148-020-0820-0

Cited by 68 publications

(57 citation statements)

References 72 publications

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“…Of the 172 CpGs included in the DNAmPACKYRS metric, the cg05575921 site, corresponding to the Aryl Hydrocarbon Receptor Repressor (AHRR) gene, was of particular interest in light of recent evidence suggesting a role in post-traumatic stress disorder(31,32). To explore if the cg05575921 methylation site might be contributing to differences in DNAmPACKYRS between MDD and HC independent of smoking exposure, we assessed differences in cg05575921 methylation 1) associated with smoking, and 2) between MDD and HC.…”

Section: Resultsmentioning

confidence: 99%

“…Our pattern of findings is also consistent with those of Lu et al in their original publication on GrimAge, where they demonstrated that DNAmPACKYRS predicted lifespan in never smokers(15), suggesting that this composite measure of methylation at 172 CpG sites reflects changes in underlying biological processes not specific to tobacco use. Of these sites, the cg05575921 site and its associated gene – the Aryl Hydrocarbon Receptor Repressor (AHRR) – stand out as potentially relevant to the pathophysiology of psychiatric disease(31,32) and aging(36,37). We compared methylation at this site between MDD and HC and found no significant differences.…”

Section: Discussionmentioning

confidence: 99%

“…We compared methylation at this site between MDD and HC and found no significant differences. Nonetheless, in light of evidence for a role the AHRR in atherosclerosis(36,37) and PTSD(31,32) in human studies, in conjunction with evidence from animal studies implicating dysfunction of the AHRR’s target – the Aryl Hydrocarbon Receptor – in aging (notably, brain aging)(38) and neuroinflammation(39), the AHRR remains an interesting and worthwhile target for further research in depression and other psychiatric diseases.…”

Section: Discussionmentioning

confidence: 99%

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“GrimAge,” an epigenetic predictor of mortality, is accelerated in Major Depressive Disorder

Protsenko

Yang

Nier

et al. 2020

Preprint

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Major Depressive Disorder (MDD) is associated with premature mortality and is an independent risk factor for a broad range of diseases, especially those associated with aging, such as cardiovascular disease, diabetes, and Alzheimer’s Disease. However, the pathophysiology underlying increased rates of somatic disease in MDD remains unknown. It has been proposed that MDD represents a state of accelerated cellular aging, and several measures of cellular aging have been developed in recent years. Among such metrics, estimators of biological age based on predictable age-related patterns of DNA methylation (DNAm), so called ‘epigenetic clocks’, have shown particular promise for their ability to capture accelerated aging in psychiatric disease. The recently developed DNAm metric known as ‘GrimAge’ is unique in that it was trained on time-to-death data and has outperformed its predecessors in predicting both morbidity and mortality. Yet, GrimAge has not been investigated in MDD. Here we measured GrimAge in 49 somatically healthy unmedicated individuals with MDD and 60 age-matched healthy controls. We found that individuals with MDD exhibited significantly greater GrimAge relative to their chronological age (‘AgeAccelGrim’) compared to healthy controls (p=0.001), with a median of two years of excess cellular aging. This difference remained significant after controlling for sex, current smoking status and body-mass index (p=0.015). These findings are consistent with prior suggestions of accelerated cellular aging in MDD, but are the first to demonstrate this with an epigenetic metric predictive of premature mortality.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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“GrimAge,” an epigenetic predictor of mortality, is accelerated in Major Depressive Disorder

Protsenko

Yang

Nier

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…However, two recently published studies have provided insight into this question. The first sought to identify DNA methylation differences associated with PTSD in blood of 378 PTSD cases and 135 controls from the Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS) cohort 25 . This study used a methylation-based score for smoking as a covariate, and still reported a significant association between PTSD and cg05575921 ( AHRR ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

Self Cite

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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.

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“…Similar epigenetic signatures have been discovered in humans with a history of childhood abuse [ 68 ]. Epigenetic biomarkers have been developed for diagnosis of metabolic diseases and, perhaps of most interest here, neuropsychiatric disorders in humans [ 69 , 70 , 71 ]. In pigs, the influence of early-life stress has been extensively studied and documented (reviewed in [ 72 ]; however, with few exceptions [ 73 ], the epigenome alterations remain largely unexplored.…”

Section: Biomarkers For Stress Resilience In Farm Animalsmentioning

confidence: 99%

Omics Application in Animal Science—A Special Emphasis on Stress Response and Damaging Behaviour in Pigs

Kasper

Ribeiro

Almeida

et al. 2020

Genes

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Increasing stress resilience of livestock is important for ethical and profitable meat and dairy production. Susceptibility to stress can entail damaging behaviours, a common problem in pig production. Breeding animals with increased stress resilience is difficult for various reasons. First, studies on neuroendocrine and behavioural stress responses in farm animals are scarce, as it is difficult to record adequate phenotypes under field conditions. Second, damaging behaviours and stress susceptibility are complex traits, and their biology is not yet well understood. Dissecting complex traits into biologically better defined, heritable and easily measurable proxy traits and developing biomarkers will facilitate recording these traits in large numbers. High-throughput molecular technologies (“omics”) study the entirety of molecules and their interactions in a single analysis step. They can help to decipher the contributions of different physiological systems and identify candidate molecules that are representative of different physiological pathways. Here, we provide a general overview of different omics approaches and we give examples of how these techniques could be applied to discover biomarkers. We discuss the genetic dissection of the stress response by different omics techniques and we provide examples and outline potential applications of omics tools to understand and prevent outbreaks of damaging behaviours.

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

Cited by 68 publications

References 72 publications

“GrimAge,” an epigenetic predictor of mortality, is accelerated in Major Depressive Disorder

“GrimAge,” an epigenetic predictor of mortality, is accelerated in Major Depressive Disorder

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

Omics Application in Animal Science—A Special Emphasis on Stress Response and Damaging Behaviour in Pigs

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