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Epigenetics of Posttraumatic Stress Disorder: Current Evidence, Challenges, and Future Directions

  • Anthony S. Zannas
    Affiliations
    Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

    Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina
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  • Nadine Provençal
    Affiliations
    Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
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  • Elisabeth B. Binder
    Correspondence
    Address correspondence to Elisabeth Binder, M.D., Ph.D., Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, Munich 80804, Germany
    Affiliations
    Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

    Department of Psychiatry and Behavioral Sciences, Emory University Medical School, Atlanta, Georgia
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      Abstract

      Posttraumatic stress disorder (PTSD) is a stress-related psychiatric disorder that is thought to emerge from complex interactions among traumatic events and multiple genetic factors. Epigenetic regulation lies at the heart of these interactions and mediates the lasting effects of the environment on gene regulation. An increasing body of evidence in human subjects with PTSD supports a role for epigenetic regulation of distinct genes and pathways in the pathogenesis of PTSD. The role of epigenetic regulation is further supported by studies examining fear conditioning in rodent models. Although this line of research offers an exciting outlook for future epigenetic research in PTSD, important limitations include the tissue specificity of epigenetic modifications, the phenomenologic definition of the disorder, and the challenge of translating molecular evidence across species. These limitations call for studies that combine data from postmortem human brain tissue and animal models, assess longitudinal epigenetic changes in living subjects, and examine dimensional phenotypes in addition to diagnoses. Moreover, examining the environmental, genetic, and epigenetic factors that promote resilience to trauma may lead to important advances in the field.

      Keywords

      Traumatic events, as defined by DSM-IV, have been estimated to occur in 90% of individuals in the general population at some point in their lives (
      • Breslau N.
      • Kessler R.C.
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      • Davis G.C.
      • Andreski P.
      Trauma and posttraumatic stress disorder in the community: The 1996 Detroit Area Survey of Trauma.
      ). However, only a small percentage of traumatized individuals meet the criteria for posttraumatic stress disorder (PTSD) (
      • Galea S.
      • Nandi A.
      • Vlahov D.
      The epidemiology of post-traumatic stress disorder after disasters.
      ), and some individuals have been reported to undergo positive psychological changes after trauma, denoted as posttraumatic growth (
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      • Xu J.
      • Liu H.
      • Liu D.
      Posttraumatic stress disorder and posttraumatic growth among adult survivors of Wenchuan earthquake after 1 year: Prevalence and correlates.
      ). The ability to predict individual responses to traumatic events, which are ubiquitous and often inevitable, could offer the opportunity to target preventive strategies and early interventions to vulnerable individuals.
      Predictive ability can be enhanced by gaining insights into the mechanisms that contribute to PTSD development after exposure to trauma. PTSD, similar to other diagnostic entities in psychiatry, is clinically heterogeneous and defined on a phenomenologic basis, not adequately reflecting the underlying pathophysiology, a limitation that has been increasingly recognized and attributed to knowledge gaps in the etiological underpinnings of psychiatric disorders (
      • Casey B.J.
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      • Lee F.S.
      • Ressler K.J.
      DSM-5 and RDoC: Progress in psychiatry research?.
      ). Elucidating the molecular mechanisms underlying PTSD could contribute to a more accurate diagnostic definition and ultimately to the development of individualized treatment interventions.
      Among the molecular processes implicated in PTSD and related conditions, this review focuses on epigenetics. The role of epigenetic regulation in the pathogenesis of PTSD, its potential utility for the development of biomarkers and novel treatments, and the challenges and future directions of this line of research are discussed.

      Why Examine Epigenetics in PTSD?

      The complex phenotype of PTSD is thought to emerge from interactions among multiple genetic and environmental factors. Disentangling the mechanisms through which these factors contribute to PTSD pathogenesis could enable identification of individuals predisposed to show maladaptive responses to trauma. Although heritability studies have repeatedly supported a genetic contribution to the pathogenesis of the disorder (
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      • Bradley-Davino B.
      PTSD and gene variants: New pathways and new thinking.
      ,
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      • Taylor S.
      • Vernon P.A.
      • Livesley W.J.
      Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: A twin study.
      ), efforts to consistently identify specific genetic predictors of the disorder have met with little success. This shortcoming can be attributed to several factors, including interindividual variability in the type, timing, and severity of traumatic exposure and the likely polygenic risk for the disorder with only small odds ratios for the individual variants. The awaited results of large meta-analyses performed within the Psychiatric Genomics Consortium for PTSD may lead to the identification of the first robust genetic factors.
      An important regulation of gene function and phenotypic expression occurs at the level of epigenetic regulation. Epigenetic changes consist of numerous biochemical processes, including DNA methylation and hydroxymethylation, posttranslational histone modifications, and noncoding RNAs. These processes are shown to be influenced by environmental exposure and collectively shape the transcriptional activity of genes without changing the underlying genetic code (
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      • Reinberg D.
      Molecular signals of epigenetic states.
      ,
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      Epigenetics and the environment: Emerging patterns and implications.
      ). The advent of epigenetics has challenged the previous dichotomy between “nature and nurture” because the epigenome can be viewed as a molecular interface between the environment and the genome that is influenced by genetic sequence but constantly receives regulatory feedback by environmental cues and can shape gene function and phenotypic expression in response to the environment. It is important to consider epigenetic changes in the context of the environmental exposure at the level of the neural circuit and behavior outcome.
      The possible relevance of epigenetic regulation in PTSD lies in its role in mediating long-term effects of trauma exposure on gene expression and brain function during development and in the mature central nervous system. Psychological trauma has been shown to induce epigenetic changes that can have short-term and long-lasting effects on neuronal function, brain plasticity, and behavioral adaptations to psychological stressors (
      • Zannas A.S.
      • West A.E.
      Epigenetics and the regulation of stress vulnerability and resilience.
      ,
      • Provencal N.
      • Binder E.B.
      The effects of early life stress on the epigenome: From the womb to adulthood and even before [published online ahead of print Sep 9].
      ). Epigenetic changes can provide a molecular mechanism for the development of distinct phenotypes after exposure to trauma. In most cases, trauma exposure does not lead to the development of PTSD, so that epigenetic changes following trauma exposure may accompany learning of new behaviors to avoid trauma exposure or other adaptive mechanisms. It will be important to disentangle these adaptive changes from the maladaptive ones that lead to PTSD. The difference in epigenetic changes related to disease outcome could be moderated by genetic predisposition (
      • Klengel T.
      • Mehta D.
      • Anacker C.
      • Rex-Haffner M.
      • Pruessner J.C.
      • Pariante C.M.
      • et al.
      Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.
      ), previous epigenetic embedding of another (trauma) experience, or specificity to developmental windows. These mechanistic implications and the potentially reversible nature of epigenetic changes have led to increasing interest in the epigenetics of PTSD.

      Overview of Epigenetic Studies in PTSD

      To date, most epigenetic studies in PTSD have examined the methylation status of cytosine residues of genomic DNA. The particular interest in DNA methylation in the context of PTSD was spurred by numerous studies in animals and humans showing that DNA methylation changes can be embedded by early adverse experiences and these markers may confer vulnerability to subsequent life adversity (
      • Weaver I.C.
      • Cervoni N.
      • Champagne F.A.
      • D’Alessio A.C.
      • Sharma S.
      • Seckl J.R.
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      Epigenetic programming by maternal behavior.
      ,
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      • Sasaki A.
      • D’Alessio A.C.
      • Dymov S.
      • Labonte B.
      • Szyf M.
      • et al.
      Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.
      ,
      • Murgatroyd C.
      • Patchev A.V.
      • Wu Y.
      • Micale V.
      • Bockmuhl Y.
      • Fischer D.
      • et al.
      Dynamic DNA methylation programs persistent adverse effects of early-life stress.
      ,
      • Perroud N.
      • Paoloni-Giacobino A.
      • Prada P.
      • Olie E.
      • Salzmann A.
      • Nicastro R.
      • et al.
      Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: A link with the severity and type of trauma.
      ,
      • Elliott E.
      • Ezra-Nevo G.
      • Regev L.
      • Neufeld-Cohen A.
      • Chen A.
      Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice.
      ,
      • Perroud N.
      • Rutembesa E.
      • Paoloni-Giacobino A.
      • Mutabaruka J.
      • Mutesa L.
      • Stenz L.
      • et al.
      The Tutsi genocide and transgenerational transmission of maternal stress: Epigenetics and biology of the HPA axis.
      ,
      • Roth T.L.
      • Lubin F.D.
      • Funk A.J.
      • Sweatt J.D.
      Lasting epigenetic influence of early-life adversity on the BDNF gene.
      ,
      • Provencal N.
      • Suderman M.J.
      • Guillemin C.
      • Massart R.
      • Ruggiero A.
      • Wang D.
      • et al.
      The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells.
      ,
      • Zhang T.Y.
      • Hellstrom I.C.
      • Bagot R.C.
      • Wen X.
      • Diorio J.
      • Meaney M.J.
      Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus.
      ,
      • Beach S.R.
      • Brody G.H.
      • Todorov A.A.
      • Gunter T.D.
      • Philibert R.A.
      Methylation at 5HTT mediates the impact of child sex abuse on women’s antisocial behavior: An examination of the Iowa adoptee sample.
      ,
      • Vijayendran M.
      • Beach S.R.
      • Plume J.M.
      • Brody G.H.
      • Philibert R.A.
      Effects of genotype and child abuse on DNA methylation and gene expression at the serotonin transporter.
      ). Although DNA methylation initially was thought to be a nonreversible modification based on its role in cell differentiation, it was later shown to be dynamically regulated by active enzymatic methylation and demethylation processes (
      • Telese F.
      • Gamliel A.
      • Skowronska-Krawczyk D.
      • Garcia-Bassets I.
      • Rosenfeld M.G.
      “Seq-ing” insights into the epigenetics of neuronal gene regulation.
      ,
      • Wu H.
      • Zhang Y.
      Reversing DNA methylation: Mechanisms, genomics, and biological functions.
      ). This dynamic regulation does not preclude that some stress-induced changes in DNA methylation can be stabilized and inherited as shown in animal models (
      • Dias B.G.
      • Ressler K.J.
      Parental olfactory experience influences behavior and neural structure in subsequent generations.
      ,
      • Morgan C.P.
      • Bale T.L.
      Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage.
      ,
      • Rodgers A.B.
      • Morgan C.P.
      • Bronson S.L.
      • Revello S.
      • Bale T.L.
      Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation.
      ,
      • Franklin T.B.
      • Russig H.
      • Weiss I.C.
      • Graff J.
      • Linder N.
      • Michalon A.
      • et al.
      Epigenetic transmission of the impact of early stress across generations.
      ,
      • Gapp K.
      • von Ziegler L.
      • Tweedie-Cullen R.Y.
      • Mansuy I.M.
      Early life epigenetic programming and transmission of stress-induced traits in mammals: How and when can environmental factors influence traits and their transgenerational inheritance?.
      ) and suggested in humans (
      • Perroud N.
      • Paoloni-Giacobino A.
      • Prada P.
      • Olie E.
      • Salzmann A.
      • Nicastro R.
      • et al.
      Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: A link with the severity and type of trauma.
      ,
      • Heijmans B.T.
      • Tobi E.W.
      • Stein A.D.
      • Putter H.
      • Blauw G.J.
      • Susser E.S.
      • et al.
      Persistent epigenetic differences associated with prenatal exposure to famine in humans.
      ,
      • Yehuda R.
      • Daskalakis N.P.
      • Lehrner A.
      • Desarnaud F.
      • Bader H.N.
      • Makotkine I.
      • et al.
      Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring.
      ). Identifying such DNA methylation markers may offer particular insights into the pathogenesis of the disorder.
      Human studies that have examined DNA methylation changes in PTSD are summarized in Table 1. These studies assessed peripheral blood and largely examined a priori biologically plausible candidate genes. Overall, epigenetic regulation in PTSD has been supported for genes involved in stress responses (
      • Perroud N.
      • Rutembesa E.
      • Paoloni-Giacobino A.
      • Mutabaruka J.
      • Mutesa L.
      • Stenz L.
      • et al.
      The Tutsi genocide and transgenerational transmission of maternal stress: Epigenetics and biology of the HPA axis.
      ,
      • Yehuda R.
      • Daskalakis N.P.
      • Lehrner A.
      • Desarnaud F.
      • Bader H.N.
      • Makotkine I.
      • et al.
      Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring.
      ,
      • Yehuda R.
      • Daskalakis N.P.
      • Desarnaud F.
      • Makotkine I.
      • Lehrner A.L.
      • Koch E.
      • et al.
      Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD.
      ,
      • Yehuda R.
      • Flory J.D.
      • Bierer L.M.
      • Henn-Haase C.
      • Lehrner A.
      • Desarnaud F.
      • et al.
      Lower methylation of glucocorticoid receptor gene promoter 1 in peripheral blood of veterans with posttraumatic stress disorder.
      ,
      • Ressler K.J.
      • Mercer K.B.
      • Bradley B.
      • Jovanovic T.
      • Mahan A.
      • Kerley K.
      • et al.
      Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.
      ,
      • Labonte B.
      • Azoulay N.
      • Yerko V.
      • Turecki G.
      • Brunet A.
      Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder.
      ,
      • Vukojevic V.
      • Kolassa I.T.
      • Fastenrath M.
      • Gschwind L.
      • Spalek K.
      • Milnik A.
      • et al.
      Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors.
      ), neurotransmitter activity (
      • Koenen K.C.
      • Uddin M.
      • Chang S.C.
      • Aiello A.E.
      • Wildman D.E.
      • Goldmann E.
      • et al.
      SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder.
      ,
      • Chang S.C.
      • Koenen K.C.
      • Galea S.
      • Aiello A.E.
      • Soliven R.
      • Wildman D.E.
      • et al.
      Molecular variation at the SLC6A3 locus predicts lifetime risk of PTSD in the Detroit Neighborhood Health Study.
      ,
      • Norrholm S.D.
      • Jovanovic T.
      • Smith A.K.
      • Binder E.
      • Klengel T.
      • Conneely K.
      • et al.
      Differential genetic and epigenetic regulation of catechol-O-methyltransferase is associated with impaired fear inhibition in posttraumatic stress disorder.
      ,
      • van I.M.H.
      • Caspers K.
      • Bakermans-Kranenburg M.J.
      • Beach S.R.
      • Philibert R.
      Methylation matters: Interaction between methylation density and serotonin transporter genotype predicts unresolved loss or trauma.
      ), immune regulation (
      • Rusiecki J.A.
      • Byrne C.
      • Galdzicki Z.
      • Srikantan V.
      • Chen L.
      • Poulin M.
      • et al.
      PTSD and DNA methylation in select immune function gene promoter regions: A repeated measures case-control study of U.S. military service members.
      ), or repetitive genomic elements (
      • Rusiecki J.A.
      • Chen L.
      • Srikantan V.
      • Zhang L.
      • Yan L.
      • Polin M.L.
      • et al.
      DNA methylation in repetitive elements and post-traumatic stress disorder: A case-control study of US military service members.
      ). Far fewer studies have followed an epigenome-wide approach or used epigenome-wide markers (
      • Mehta D.
      • Klengel T.
      • Conneely K.N.
      • Smith A.K.
      • Altmann A.
      • Pace T.W.
      • et al.
      Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder.
      ,
      • Uddin M.
      • Aiello A.E.
      • Wildman D.E.
      • Koenen K.C.
      • Pawelec G.
      • de Los Santos R.
      • et al.
      Epigenetic and immune function profiles associated with posttraumatic stress disorder.
      ,
      • Smith A.K.
      • Conneely K.N.
      • Kilaru V.
      • Mercer K.B.
      • Weiss T.E.
      • Bradley B.
      • et al.
      Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder.
      ,
      • Boks M.P.
      • Mierlo H.C.
      • Rutten B.P.
      • Radstake T.R.
      • De Witte L.
      • Geuze E.
      • et al.
      Longitudinal changes of telomere length and epigenetic age related to traumatic stress and post-traumatic stress disorder.
      ). The latter approaches offer a less biased way of interrogating the epigenome and the potential to identify novel candidate genes and biological pathways implicated in the pathogenesis of PTSD. The potential mechanisms, limitations, and implications of these epigenetic findings and potential directions for future research are discussed in more detail in the following sections.
      Table 1Human Studies Supporting the Role of DNA Methylation in PTSD
      ReferenceSample Size (N)ApproachIdentified Genetic LociMethod of DNA Methylation AssessmentPrimary Finding
      Uddin et al., 2010 (
      • Uddin M.
      • Aiello A.E.
      • Wildman D.E.
      • Koenen K.C.
      • Pawelec G.
      • de Los Santos R.
      • et al.
      Epigenetic and immune function profiles associated with posttraumatic stress disorder.
      )
      100Epigenome-wideGenes involved in innate and adaptive immune responsesBisulfite followed by Infinium HumanMethylation 27K BeadChip (Illumina, San Diego, California)Immune system functions are overrepresented among the uniquely unmethylated genes in subjects with PTSD
      Koenen et al., 2011 (
      • Koenen K.C.
      • Uddin M.
      • Chang S.C.
      • Aiello A.E.
      • Wildman D.E.
      • Goldmann E.
      • et al.
      SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder.
      )
      100Candidate genetic lociSLC6A4Bisulfite followed by Infinium HumanMethylation 27K BeadChipAt high numbers of traumatic events, lower SLC6A4 methylation levels increase risk for PTSD, whereas higher methylation levels protect from the disorder
      Uddin et al., 2011 (
      • Uddin M.
      • Galea S.
      • Chang S.C.
      • Aiello A.E.
      • Wildman D.E.
      • de los Santos R.
      • et al.
      Gene expression and methylation signatures of MAN2C1 are associated with PTSD.
      )
      100Candidate genetic lociMAN2C1Bisulfite followed by Infinium HumanMethylation 27K BeadChipIncreased lifetime risk for PTSD in individuals with higher MAN2C1 methylation levels and exposed to greater numbers of potentially traumatic events
      Smith et al., 2011 (
      • Smith A.K.
      • Conneely K.N.
      • Kilaru V.
      • Mercer K.B.
      • Weiss T.E.
      • Bradley B.
      • et al.
      Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder.
      )
      110Epigenome-wideTPR, CLEC9A, APC5, ANXA2, TLR8Bisulfite followed by Infinium HumanMethylation 27K BeadChipPTSD is associated with increased global methylation and differential methylation of genes associated with inflammation
      Ressler et al., 2011 (
      • Ressler K.J.
      • Mercer K.B.
      • Bradley B.
      • Jovanovic T.
      • Mahan A.
      • Kerley K.
      • et al.
      Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.
      )
      94Candidate genetic lociADCYAP1R1Bisulfite followed by Infinium HumanMethylation 27K BeadChipADCYAP1R1 methylation levels were associated with PTSD symptoms in subjects with heavy exposure to trauma
      Rusiecki et al., 2012 (
      • Rusiecki J.A.
      • Chen L.
      • Srikantan V.
      • Zhang L.
      • Yan L.
      • Polin M.L.
      • et al.
      DNA methylation in repetitive elements and post-traumatic stress disorder: A case-control study of US military service members.
      )
      150Candidate genetic lociLINE-1, AluBisulfite mapping using pyrosequencingPostdeployment hypermethylation of Alu in veterans with PTSD and LINE-1 in veterans without PTSD
      Chang et al., 2012 (
      • Chang S.C.
      • Koenen K.C.
      • Galea S.
      • Aiello A.E.
      • Soliven R.
      • Wildman D.E.
      • et al.
      Molecular variation at the SLC6A3 locus predicts lifetime risk of PTSD in the Detroit Neighborhood Health Study.
      )
      83Candidate genetic lociSLC6A3Bisulfite followed by Infinium HumanMethylation 27K BeadChipNine-repeat allele of SLC6A3 doubles PTSD risk only in the presence of high SLC6A3 promoter methylation levels
      Norrholm et al., 2013 (
      • Norrholm S.D.
      • Jovanovic T.
      • Smith A.K.
      • Binder E.
      • Klengel T.
      • Conneely K.
      • et al.
      Differential genetic and epigenetic regulation of catechol-O-methyltransferase is associated with impaired fear inhibition in posttraumatic stress disorder.
      )
      270Candidate genetic lociCOMTBisulfite followed by Infinium HumanMethylation 27K BeadChipHigher methylation levels of the COMT promoter are associated with impaired fear inhibition. The Met/Met COMT genotype was associated with increased COMT promoter methylation
      Klengel et al., 2013 (
      • Klengel T.
      • Mehta D.
      • Anacker C.
      • Rex-Haffner M.
      • Pruessner J.C.
      • Pariante C.M.
      • et al.
      Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.
      )
      76Candidate genetic lociFKBP5Bisulfite mapping using pyrosequencingAllele-specific childhood trauma–dependent FKBP5 demethylation increases PTSD risk
      Rusiecki et al., 2013 (
      • Rusiecki J.A.
      • Byrne C.
      • Galdzicki Z.
      • Srikantan V.
      • Chen L.
      • Poulin M.
      • et al.
      PTSD and DNA methylation in select immune function gene promoter regions: A repeated measures case-control study of U.S. military service members.
      )
      150Candidate genetic lociIGF2, H19, IL8, IL16, IL18Bisulfite mapping using pyrosequencingDeployment resulted in increased IL18 methylation in veterans who developed PTSD, but decreased H19 and IL18 methylation levels in veterans without PTSD
      Mehta et al., 2013 (
      • Mehta D.
      • Klengel T.
      • Conneely K.N.
      • Smith A.K.
      • Altmann A.
      • Pace T.W.
      • et al.
      Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder.
      )
      169Epigenome-wideEnrichment of overlapping and nonoverlapping pathways between groupsBisulfite followed by Infinium HumanMethylation 27K BeadChipCompared with PTSD cases without childhood abuse, PTSD cases with childhood abuse show distinct and almost nonoverlapping gene expression and DNA methylation profiles
      Uddin et al., 2013 (
      • Uddin M.
      • Galea S.
      • Chang S.C.
      • Koenen K.C.
      • Goldmann E.
      • Wildman D.E.
      • et al.
      Epigenetic signatures may explain the relationship between socioeconomic position and risk of mental illness: Preliminary findings from an urban community-based sample.
      )
      100Epigenome-wideSeveral genes involved in neuronal function and synaptic transmissionBisulfite followed by Infinium HumanMethylation 27K BeadChipSocioeconomic position moderates the relationship between methylation levels of genes involved in neuronal function and PTSD symptoms
      Yehuda et al., 2013 (
      • Yehuda R.
      • Daskalakis N.P.
      • Desarnaud F.
      • Makotkine I.
      • Lehrner A.L.
      • Koch E.
      • et al.
      Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD.
      )
      16Candidate genetic lociNR3C1, FKBP5Bisulfite mapping using clonal sequencingPretreatment methylation levels of the NR3C1 exon 1F predicted response to prolonged exposure psychotherapy, and changes in methylation of the FKBP5 promoter occurred concomitantly with recovery from PTSD
      Labonte et al., 2014 (
      • Labonte B.
      • Azoulay N.
      • Yerko V.
      • Turecki G.
      • Brunet A.
      Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder.
      )
      46Candidate genetic lociNR3C1Sequenom EpiTYPER (Agena Bioscience, San Diego, California)PTSD is associated with higher NR3C1 expression and lower overall methylation levels in 1B and 1C promoters. Methylation levels were inversely correlated with NR3C1 expression
      Yehuda et al., 2014 (
      • Yehuda R.
      • Daskalakis N.P.
      • Lehrner A.
      • Desarnaud F.
      • Bader H.N.
      • Makotkine I.
      • et al.
      Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring.
      )
      95Candidate genetic lociNR3C1Bisulfite mapping using clonal sequencingOffspring with paternal PTSD showed higher NR3C1 1F promoter methylation if maternal PTSD was not present. Offspring with maternal and paternal PTSD showed lower methylation
      Yehuda et al., 2014 (
      • Yehuda R.
      • Flory J.D.
      • Bierer L.M.
      • Henn-Haase C.
      • Lehrner A.
      • Desarnaud F.
      • et al.
      Lower methylation of glucocorticoid receptor gene promoter 1 in peripheral blood of veterans with posttraumatic stress disorder.
      )
      122Candidate genetic lociNR3C1Bisulfite mapping using clonal sequencingLower NR3C1 1F promoter methylation was observed in combat veterans with PTSD compared with combat veterans without PTSD. NR3C1 1F promoter methylation inversely correlated with symptoms
      Vukojevic et al., 2014 (
      • Vukojevic V.
      • Kolassa I.T.
      • Fastenrath M.
      • Gschwind L.
      • Spalek K.
      • Milnik A.
      • et al.
      Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors.
      )
      152Candidate genetic lociNR3C1Bisulfite mapping using pyrosequencingIn male but not female survivors of the genocide in Rwanda, increased NR3C1 1F promoter methylation was associated with less PTSD risk and re-experiencing symptoms, lower NR3C1 expression, reduced picture recognition, and differences in recognition memory-related brain activity
      Boks et al., 2015 (
      • Boks M.P.
      • Mierlo H.C.
      • Rutten B.P.
      • Radstake T.R.
      • De Witte L.
      • Geuze E.
      • et al.
      Longitudinal changes of telomere length and epigenetic age related to traumatic stress and post-traumatic stress disorder.
      )
      96Use of epigenome-wide based marker (“epigenetic clock”)Bisulfite followed by Infinium HumanMethylation 450K BeadChipExposure to military combat trauma was significantly associated with accelerated epigenetic aging, whereas development of PTSD symptoms was inversely correlated with epigenetic aging
      Studies are reported in chronologic order. Sample sizes reflect the number of subjects with DNA methylation data that were included in the respective analyses. All studies examined peripheral blood from human subjects except for the study by Vukojevic et al., 2014 (
      • Vukojevic V.
      • Kolassa I.T.
      • Fastenrath M.
      • Gschwind L.
      • Spalek K.
      • Milnik A.
      • et al.
      Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors.
      ), which examined saliva. Presented studies were retrieved by searching the National Library of Medicine PubMed database using the terms “DNA methylation,” “epigenetics,” “histone modifications,” “histone acetylation,” “histone deacetylation,” “histone methylation,” “histone demethylation,” “epigenetic modifications,” and “epigenetic changes” for the epigenetic component combined with the terms “PTSD,” “posttraumatic stress disorder,” and “posttraumatic growth.” This search strategy and further reading of the literature yielded 18 original articles in humans published between 2009 and 2015 that are summarized in the table.
      PTSD, posttraumatic stress disorder.

      Examining Epigenetic Mechanisms of PTSD in Humans

      Human studies are crucial for understanding epigenetic processes in PTSD, but the tissue-specific nature of epigenetic modifications and the inability to access brain tissue of living humans impede the ability of such studies to offer mechanistic insights. This shortcoming may be partially overcome by examining postmortem brain tissue. The need for postmortem studies in PTSD has long been highlighted (
      • Osuch E.
      • Ursano R.
      • Li H.
      • Webster M.
      • Hough C.
      • Fullerton C.
      • et al.
      Brain environment interactions: Stress, posttraumatic stress disorder, and the need for a postmortem brain collection.
      ), but, to our knowledge, no studies so far have examined epigenetic markers in postmortem brains of subjects with PTSD. Such studies could offer valuable insights into brain region–specific epigenetic markers that might show differences between patients with PTSD and control subjects. Analysis of postmortem data from different brain regions could be used to understand how epigenetic regulation works at a circuit, brain region, or whole-brain level in PTSD. System-level approaches using postmortem tissue have shown promise in other fields of psychiatric research (
      • Roussos P.
      • Katsel P.
      • Davis K.L.
      • Siever L.J.
      • Haroutunian V.
      A system-level transcriptomic analysis of schizophrenia using postmortem brain tissue samples.
      ). Despite these strengths, postmortem studies would still face important limitations, including the confounding effect of lifestyle factors known to affect epigenetic changes and the inability to discern the temporal relationship among trauma exposure, epigenetic modifications, and PTSD development.
      The importance of examining living subjects and the demand for easily accessible biomarkers that can be used in clinical settings necessitate the use of peripheral tissue. The premise is that epigenetic changes in peripheral tissues, such as in blood or saliva, either could be driven by processes initiated in the central nervous system and may reflect similar changes in the brain or could be peripheral disease-associated changes that may or may not be involved in the pathogenesis of the disorder and can serve as biomarkers. Two potential mechanisms that could mediate effects of trauma exposure on the periphery include persistent neuroendocrine alterations, in particular, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and immune dysregulation.

      Epigenetic Regulation of the HPA Axis as a “Window to the Brain”

      HPA axis dysregulation has been repeatedly linked with trauma exposure and stress-related psychiatric disorders (
      • Holsboer F.
      The corticosteroid receptor hypothesis of depression.
      ,
      • Shea A.
      • Walsh C.
      • Macmillan H.
      • Steiner M.
      Child maltreatment and HPA axis dysregulation: Relationship to major depressive disorder and post traumatic stress disorder in females.
      ), and although discrepancies exist among studies, PTSD has been associated with suppressed cortisol levels that have been attributed to hypersensitivity of the glucocorticoid receptor (GR) and enhanced negative feedback inhibition (
      • Mehta D.
      • Binder E.B.
      Gene x environment vulnerability factors for PTSD: The HPA-axis.
      ,
      • Yehuda R.
      Status of glucocorticoid alterations in post-traumatic stress disorder.
      ). These HPA axis abnormalities may drive persistent changes of the neuroendocrine milieu, which could effect epigenetic changes in cells throughout the body. A detailed description of the HPA axis is beyond the scope of this article and has been provided elsewhere (
      • Zannas A.S.
      • West A.E.
      Epigenetics and the regulation of stress vulnerability and resilience.
      ,
      • Chrousos G.P.
      • Gold P.W.
      The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis.
      ). The HPA axis culminates in peripheral secretion of glucocorticoids. After activation by glucocorticoids, the GR dissociates from this complex, translocates into the nucleus, and transactivates or transrepresses a large number of glucocorticoid-responsive genes. In addition to dynamic changes in gene expression, repetitious transactivation or transrepression of GR-responsive genes in the periphery may result in lasting changes in DNA methylation. Such changes have been observed in glucocorticoid-responsive genes after exposure to glucocorticoids (
      • Klengel T.
      • Mehta D.
      • Anacker C.
      • Rex-Haffner M.
      • Pruessner J.C.
      • Pariante C.M.
      • et al.
      Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.
      ,
      • Lee R.S.
      • Tamashiro K.L.
      • Yang X.
      • Purcell R.H.
      • Huo Y.
      • Rongione M.
      • et al.
      A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice.
      ) and have been suggested to correlate with similar changes in specific brain regions (
      • Ewald E.R.
      • Wand G.S.
      • Seifuddin F.
      • Yang X.
      • Tamashiro K.L.
      • Potash J.B.
      • et al.
      Alterations in DNA methylation of Fkbp5 as a determinant of blood-brain correlation of glucocorticoid exposure.
      ).
      Among genes involved in regulation of the HPA axis, the most extensively studied is the gene encoding the GR, NR3C1, which is regulated through multiple promoter regions located in its noncoding exon 1 variants that contain numerous glucocorticoid response elements. Particular attention was drawn to this locus by studies in rodents and humans linking early life adversity with increased methylation levels of the NR3C1 exon 1F promoter (Nr3c1 17 in rodents) in peripheral blood and in brain tissue (
      • Weaver I.C.
      • Cervoni N.
      • Champagne F.A.
      • D’Alessio A.C.
      • Sharma S.
      • Seckl J.R.
      • et al.
      Epigenetic programming by maternal behavior.
      ,
      • McGowan P.O.
      • Sasaki A.
      • D’Alessio A.C.
      • Dymov S.
      • Labonte B.
      • Szyf M.
      • et al.
      Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.
      ,
      • Perroud N.
      • Paoloni-Giacobino A.
      • Prada P.
      • Olie E.
      • Salzmann A.
      • Nicastro R.
      • et al.
      Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: A link with the severity and type of trauma.
      ,
      • Tyrka A.R.
      • Price L.H.
      • Marsit C.
      • Walters O.C.
      • Carpenter L.L.
      Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults.
      ). In a study examining combat veterans, subjects with PTSD were shown to have lower peripheral blood methylation levels in the NR3C1 exon 1F promoter compared with combat veterans without PTSD (
      • Yehuda R.
      • Daskalakis N.P.
      • Desarnaud F.
      • Makotkine I.
      • Lehrner A.L.
      • Koch E.
      • et al.
      Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD.
      ). In addition, NR3C1 exon 1F methylation inversely correlated with dexamethasone suppression of cortisol and PTSD symptoms. In a separate study, increase in NR3C1 exon 1F methylation levels predicted favorable PTSD response to prolonged exposure psychotherapy, supporting the usefulness of NR3C1 methylation as a biomarker for the disorder (
      • Yehuda R.
      • Daskalakis N.P.
      • Desarnaud F.
      • Makotkine I.
      • Lehrner A.L.
      • Koch E.
      • et al.
      Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD.
      ). In line with these findings, civilians with lifetime diagnosis of PTSD were shown to have lower T-cell NR3C1 exon 1B and 1C methylation levels and higher GR expression, but no differences were observed between individuals with current and remitted PTSD (
      • Labonte B.
      • Azoulay N.
      • Yerko V.
      • Turecki G.
      • Brunet A.
      Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder.
      ).
      Another glucocorticoid-responsive gene that has drawn increasing attention is the gene encoding FK506 binding protein 51 (FKBP51), FKBP5. Among other functions, FK506 binding protein 51—induced by GR activation—also acts as a cochaperone of the GR, creating an intracellular ultrashort negative feedback loop that decreases GR signaling and maintains homeostasis of the HPA axis (
      • Zannas A.S.
      • Binder E.B.
      Gene-environment interactions at the FKBP5 locus: Sensitive periods, mechanisms and pleiotropism.
      ,
      • Zhang X.
      • Clark A.F.
      • Yorio T.
      FK506-binding protein 51 regulates nuclear transport of the glucocorticoid receptor beta and glucocorticoid responsiveness.
      ,
      • Wochnik G.M.
      • Ruegg J.
      • Abel G.A.
      • Schmidt U.
      • Holsboer F.
      • Rein T.
      FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells.
      ). FKBP51 is an important modulator of GR activity and stress responsivity. The role of the FKBP5 gene in PTSD has been supported by many studies conducted by our group and others showing that FKBP5 alleles confer increased risk for PTSD, especially in the context of early adversity, and are associated with worse PTSD symptoms (
      • Xie P.
      • Kranzler H.R.
      • Poling J.
      • Stein M.B.
      • Anton R.F.
      • Farrer L.A.
      • et al.
      Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder.
      ,
      • Binder E.B.
      • Bradley R.G.
      • Liu W.
      • Epstein M.P.
      • Deveau T.C.
      • Mercer K.B.
      • et al.
      Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults.
      ,
      • Boscarino J.A.
      • Erlich P.M.
      • Hoffman S.N.
      • Zhang X.
      Higher FKBP5, COMT, CHRNA5, and CRHR1 allele burdens are associated with PTSD and interact with trauma exposure: Implications for neuropsychiatric research and treatment.
      ). We further showed that not only genetic but also epigenetic regulation of the FKBP5 gene in response to early trauma is implicated in PTSD pathogenesis. In particular, cytosine-phosphate-guanine (CpG) sites located near glucocorticoid response elements of the intron 7 regulatory region of the FKBP5 gene were shown to undergo demethylation in response to childhood, but not adulthood, trauma in risk allele carriers (
      • Klengel T.
      • Mehta D.
      • Anacker C.
      • Rex-Haffner M.
      • Pruessner J.C.
      • Pariante C.M.
      • et al.
      Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.
      ). Similar DNA methylation changes were observed after glucocorticoid exposure in human progenitor hippocampal neuronal cells, suggesting that FKBP5 demethylation in response to excessive glucocorticoids release following early life trauma may represent an epigenetic signature that is stable across tissues in humans. Methylation levels of the FKBP5 promoter also were shown to accompany treatment response in PTSD, suggesting potential usefulness of this marker in tracking disease course (
      • Yehuda R.
      • Daskalakis N.P.
      • Lehrner A.
      • Desarnaud F.
      • Bader H.N.
      • Makotkine I.
      • et al.
      Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring.
      ). These preliminary findings await replication in a larger sample.
      Finally, epigenetic regulation in the context of PTSD has been examined at the stress-responsive genes that encode the pituitary adenylate cyclase–activating polypeptide (ADCYAP1) and its receptor (ADCYAP1R1), which, among its pleiotropic functions, modulates stress responses. In peripheral blood, pituitary adenylate cyclase–activating polypeptide levels were associated with PTSD diagnosis and symptoms in highly traumatized female subjects, and ADCYAP1R1 CpG island methylation levels predicted PTSD symptoms in both sexes (
      • Ressler K.J.
      • Mercer K.B.
      • Bradley B.
      • Jovanovic T.
      • Mahan A.
      • Kerley K.
      • et al.
      Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.
      ). These results were corroborated by rodent experiments showing induction of ADCYAP1R1 transcription by fear conditioning, an established animal model of PTSD. Future studies are needed to assess to what extent epigenetic changes of HPA genes in the periphery reflect alterations in brain tissue and whether such changes contribute to the pathogenesis of PTSD or merely represent an epiphenomenon of endocrine dysregulation.

      Epigenetics and Immune Dysregulation in PTSD

      A growing body of evidence has linked PTSD with alterations in immune function (
      • Pace T.W.
      • Heim C.M.
      A short review on the psychoneuroimmunology of posttraumatic stress disorder: From risk factors to medical comorbidities.
      ,
      • Gill J.M.
      • Saligan L.
      • Woods S.
      • Page G.
      PTSD is associated with an excess of inflammatory immune activities.
      ,
      • Danese A.
      • Moffitt T.E.
      • Harrington H.
      • Milne B.J.
      • Polanczyk G.
      • Pariante C.M.
      • et al.
      Adverse childhood experiences and adult risk factors for age-related disease: Depression, inflammation, and clustering of metabolic risk markers.
      ,
      • Danese A.
      • McEwen B.S.
      Adverse childhood experiences, allostasis, allostatic load, and age-related disease.
      ,
      • Danese A.
      • Pariante C.M.
      • Caspi A.
      • Taylor A.
      • Poulton R.
      Childhood maltreatment predicts adult inflammation in a life-course study.
      ,
      • Pace T.W.
      • Wingenfeld K.
      • Schmidt I.
      • Meinlschmidt G.
      • Hellhammer D.H.
      • Heim C.M.
      Increased peripheral NF-kappaB pathway activity in women with childhood abuse-related posttraumatic stress disorder.
      ). This relationship has been suggested to be twofold: 1) Trauma exposure and PTSD may dysregulate peripheral immune function via persistent disturbances of the HPA axis, and 2) immune dysregulation in the periphery can contribute to vulnerability for the development of PTSD via alterations in brain function. It is plausible that traumatic exposure induces lasting epigenetic signatures at immune-related genetic loci that may lead to immune dysregulation and increased risk for PTSD.
      Epigenetic changes in immune-related genes have been observed in numerous studies examining DNA methylation changes of immune-related genes as well as genome-wide studies that identified epigenetic alterations in biological pathways involved in immune function. Methylation levels of the gene encoding interleukin (IL)-18 were found to increase after deployment in military service members who developed PTSD, but to decrease in deployed subjects who did not develop PTSD (
      • Rusiecki J.A.
      • Byrne C.
      • Galdzicki Z.
      • Srikantan V.
      • Chen L.
      • Poulin M.
      • et al.
      PTSD and DNA methylation in select immune function gene promoter regions: A repeated measures case-control study of U.S. military service members.
      ). Because IL-18 is a cytokine that has been linked with risk for cardiovascular disease (
      • Troseid M.
      • Seljeflot I.
      • Arnesen H.
      The role of interleukin-18 in the metabolic syndrome.
      ), these findings may have implications for the elevated risk of cardiovascular risk observed in patients with PTSD (
      • Wentworth B.A.
      • Stein M.B.
      • Redwine L.S.
      • Xue Y.
      • Taub P.R.
      • Clopton P.
      • et al.
      Post-traumatic stress disorder: A fast track to premature cardiovascular disease?.
      ). In a separate study that used an unbiased, epigenome-wide approach, immune-related functions were found to be overrepresented among uniquely unmethylated genetic loci and among genes showing decreased methylation with increasing traumatic exposure (
      • Uddin M.
      • Aiello A.E.
      • Wildman D.E.
      • Koenen K.C.
      • Pawelec G.
      • de Los Santos R.
      • et al.
      Epigenetic and immune function profiles associated with posttraumatic stress disorder.
      ). Another epigenome-wide study showed that subjects with PTSD have differential methylation levels at five genes involved in inflammatory processes (TPR, CLEC9A, APC5, ANXA2, and TLR8) accompanied by increased levels of IL-4, IL-2, and tumor necrosis factor α (
      • Smith A.K.
      • Conneely K.N.
      • Kilaru V.
      • Mercer K.B.
      • Weiss T.E.
      • Bradley B.
      • et al.
      Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder.
      ).
      Nonetheless, an important limitation of these studies is the measurement of DNA methylation in either serum (
      • Rusiecki J.A.
      • Byrne C.
      • Galdzicki Z.
      • Srikantan V.
      • Chen L.
      • Poulin M.
      • et al.
      PTSD and DNA methylation in select immune function gene promoter regions: A repeated measures case-control study of U.S. military service members.
      ) or whole blood (
      • Uddin M.
      • Aiello A.E.
      • Wildman D.E.
      • Koenen K.C.
      • Pawelec G.
      • de Los Santos R.
      • et al.
      Epigenetic and immune function profiles associated with posttraumatic stress disorder.
      ,
      • Smith A.K.
      • Conneely K.N.
      • Kilaru V.
      • Mercer K.B.
      • Weiss T.E.
      • Bradley B.
      • et al.
      Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder.
      ), without controlling for cell composition. The observed findings could reflect differences in immune cell counts in PTSD, rather than trauma-specific or disease-specific epigenetic changes within a cell type. Future studies should account for cell type composition either by using bioinformatics approaches (
      • Houseman E.A.
      • Molitor J.
      • Marsit C.J.
      Reference-free cell mixture adjustments in analysis of DNA methylation data.
      ) or, optimally, by sorting cells with flow cytometry and subsequently measuring methylation levels in homogeneous cell populations.

      Translating Epigenetic Findings in PTSD

      The limitations inherent to examining mechanisms of PTSD in humans create the need for animal models with good construct validity for PTSD, such as the Pavlovian fear conditioning, avoidance learning, and predator-exposure models. A detailed description of these models and related epigenetic studies is beyond the scope of this article and has been provided elsewhere (
      • Zovkic I.B.
      • Sweatt J.D.
      Epigenetic mechanisms in learned fear: Implications for PTSD.
      ,
      • Kwapis J.L.
      • Wood M.A.
      Epigenetic mechanisms in fear conditioning: Implications for treating post-traumatic stress disorder.
      ). The rodent studies have provided valuable insights into the neural circuitry and epigenetic mechanisms that are involved in the consolidation, maintenance, and extinction of fear memories. Alterations in fear processes and related neural circuitry have been observed in animal models and subjects with PTSD, suggesting that these models might be valuable paradigms for translating research in PTSD (
      • Briscione M.A.
      • Jovanovic T.
      • Norrholm S.D.
      Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors.
      ,
      • Mahan A.L.
      • Ressler K.J.
      Fear conditioning, synaptic plasticity and the amygdala: Implications for posttraumatic stress disorder.
      ).
      Despite the role of fear processes in the pathogenesis of PTSD, studies linking peripheral epigenetic markers with fear conditioning or similar endophenotypes in humans are scarce. A study addressing this question found that in DNA from peripheral blood, higher methylation levels of CpG sites within the promoter of the gene encoding catechol-O-methyltransferase (COMT), the enzyme responsible for the inactivation of catecholamine neurotransmitters, are associated with impaired fear inhibition (
      • Norrholm S.D.
      • Jovanovic T.
      • Smith A.K.
      • Binder E.
      • Klengel T.
      • Conneely K.
      • et al.
      Differential genetic and epigenetic regulation of catechol-O-methyltransferase is associated with impaired fear inhibition in posttraumatic stress disorder.
      ). Future studies need to explore further the role of epigenetic regulation in fear conditioning and other endophenotypes with good construct validity for PTSD.

      Gene-Trauma-Epigenetic Interactions in PTSD

      An important concept that emerges from epigenetic studies in PTSD is that DNA methylation changes induced by trauma may be allele-specific and may interact in a complex manner with genetic background and trauma exposure. These interactions may affect the expression of genes involved in stress responses, neurotransmitter function, and immune regulation, eventually contributing to vulnerability/resilience endophenotypes and, ultimately, to a continuum of phenotypes ranging from PTSD to posttraumatic growth. This model of gene-trauma-epigenetic regulation in PTSD and related phenotypes and endophenotypes is described in more detail and presented schematically in Figure 1. Examining the moderating role of multiple genetic factors on trauma-mediated epigenetic changes at a systems level would require very large sample sizes and longitudinal approaches, but such an approach may pave the way for a mechanistic understanding of epigenetic regulation in PTSD.
      Figure thumbnail gr1
      Figure 1Simplified schematic representation of gene-trauma-epigenetic interactions in posttraumatic stress disorder and related phenotypes. This model is supported, for example, for the methylation status of the SLC6A4 promoter, shown to interact with the 5HTTLPR polymorphism of the gene promoter to predict psychological responses to trauma. In particular, individuals carrying the short (risk) allele were more prone to develop unresolved responses to trauma at lower methylation levels, but less prone to develop maladaptive responses at higher methylation levels (
      • van I.M.H.
      • Caspers K.
      • Bakermans-Kranenburg M.J.
      • Beach S.R.
      • Philibert R.
      Methylation matters: Interaction between methylation density and serotonin transporter genotype predicts unresolved loss or trauma.
      ). In line with these findings, the nine-repeat allele of the SLC6A3 gene was shown to double the risk for posttraumatic stress disorder only in the presence of high methylation levels of the SLC6A3 promoter (
      • Chang S.C.
      • Koenen K.C.
      • Galea S.
      • Aiello A.E.
      • Soliven R.
      • Wildman D.E.
      • et al.
      Molecular variation at the SLC6A3 locus predicts lifetime risk of PTSD in the Detroit Neighborhood Health Study.
      ). Genetic variation of the COMT gene was also shown to predict methylation levels of cytosine-phosphate-guanine (CpG) sites within the gene promoter, with higher methylation levels being associated with the Met/Met COMT genotype and predicting impaired fear inhibition (
      • Norrholm S.D.
      • Jovanovic T.
      • Smith A.K.
      • Binder E.
      • Klengel T.
      • Conneely K.
      • et al.
      Differential genetic and epigenetic regulation of catechol-O-methyltransferase is associated with impaired fear inhibition in posttraumatic stress disorder.
      ). In addition to moderation of the associations of epigenetic factors with trauma responses, genetic variants may directly moderate trauma-induced epigenetic changes. A study conducted by our group showed that exposure to childhood abuse leads to demethylation of CpG sites in the functional glucocorticoid response element in intron 7 of the FKBP5 gene only in rs1360780 T-allele (risk) carriers and not carriers of the opposite (protective) genotype (
      • Klengel T.
      • Mehta D.
      • Anacker C.
      • Rex-Haffner M.
      • Pruessner J.C.
      • Pariante C.M.
      • et al.
      Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.
      ). In this case, a genetically driven change in systemic glucocorticoid release likely alters DNA methylation changes after early trauma exposure. The risk FKBP5 allele, which is located close to a functional glucocorticoid response element, was shown to increase binding of an enhancer region located in intron 2 to the transcription start site of the gene. This leads to enhanced induction of FKBP5 expression after glucocorticoid receptor activation and subsequent glucocorticoid receptor resistance, impairing the negative feedback of the axis. In addition to such indirect effects, the effects of trauma on transcription and DNA methylation changes of sensitive loci may be directly moderated by genetic variants that affect transcription factor binding, remove or create CpG dinucleotides, or lead to altered expression of epigenetic readers and writers that command subsequent epigenetic changes. The term “epigenetic mechanisms” is used for simplification purposes and denotes the entirety of epigenetic processes, including DNA methylation, posttranslational histone modifications, noncoding RNAs, and three-dimensional changes in chromatin conformation, which act in concert to regulate gene transcription. PTG, posttraumatic growth; PTSD, posttraumatic stress disorder.

      Timing of Trauma and the Need for Longitudinal Studies

      An important point that has not been adequately addressed by previous studies is the timing of traumatic exposure and its temporal relationship to epigenetic changes and development of PTSD. Sensitive periods of trauma exposure previously were highlighted in gene-environment interaction; in particular, trauma early in life was associated with lasting epigenetic changes and more robust effects on PTSD phenotypes (
      • Provencal N.
      • Binder E.B.
      The effects of early life stress on the epigenome: From the womb to adulthood and even before [published online ahead of print Sep 9].
      ,
      • Klengel T.
      • Mehta D.
      • Anacker C.
      • Rex-Haffner M.
      • Pruessner J.C.
      • Pariante C.M.
      • et al.
      Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.
      ,
      • Zannas A.S.
      • Binder E.B.
      Gene-environment interactions at the FKBP5 locus: Sensitive periods, mechanisms and pleiotropism.
      ,
      • Heim C.
      • Binder E.B.
      Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene-environment interactions, and epigenetics.
      ,
      • Heim C.
      • Nemeroff C.B.
      The role of childhood trauma in the neurobiology of mood and anxiety disorders: Preclinical and clinical studies.
      ,
      • Widom C.S.
      Posttraumatic stress disorder in abused and neglected children grown up.
      ,
      • Bremner J.D.
      • Southwick S.M.
      • Johnson D.R.
      • Yehuda R.
      • Charney D.S.
      Childhood physical abuse and combat-related posttraumatic stress disorder in Vietnam veterans.
      ,
      • Kessler R.C.
      • Davis C.G.
      • Kendler K.S.
      Childhood adversity and adult psychiatric disorder in the US National Comorbidity Survey.
      ,
      • Molnar B.E.
      • Buka S.L.
      • Kessler R.C.
      Child sexual abuse and subsequent psychopathology: Results from the National Comorbidity Survey.
      ,
      • Teicher M.H.
      • Andersen S.L.
      • Polcari A.
      • Anderson C.M.
      • Navalta C.P.
      Developmental neurobiology of childhood stress and trauma.
      ). The importance of early trauma on epigenetic changes in PTSD was highlighted by a genome-wide study using a design that compared trauma-exposed control subjects without PTSD with patients with PTSD with or without child trauma. Patients with different traumatic histories showed distinct peripheral blood gene expression and concomitantly distinct DNA methylation profiles (
      • Mehta D.
      • Klengel T.
      • Conneely K.N.
      • Smith A.K.
      • Altmann A.
      • Pace T.W.
      • et al.
      Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder.
      ). Compared with control subjects, patients with PTSD without childhood abuse showed 244 differentially regulated transcripts, whereas patients with PTSD with childhood abuse showed 303 differentially regulated transcripts. The overlap of differentially expressed transcripts between the two PTSD subgroups was only 2%, and the DNA methylation changes that accompanied these gene-expression differences were up to 12-fold higher in the PTSD subgroup with childhood abuse. These data suggest that PTSD-related gene expression changes in peripheral blood seem to be accompanied to a different extent by DNA methylation changes depending on the prior trauma history, especially in childhood. Different epigenetic mechanisms could be implicated in the pathogenesis of the disorder depending on trauma history, and distinct biomarker profiles may be relevant to distinguish subtypes of PTSD. The importance of timing likely extends beyond childhood, and accounting for traumatic exposures at other vulnerable time points, such as during gestation or in old age, could provide invaluable insights into epigenetic mechanisms of PTSD. In addition, studies should explore the potential kindling effect of repetitive trauma exposure or the synergistic effect of early traumatic exposure and adult stressors throughout the life span. A kindling hypothesis has been supported in other psychiatric disorders (
      • Kendler K.S.
      • Thornton L.M.
      • Gardner C.O.
      Stressful life events and previous episodes in the etiology of major depression in women: An evaluation of the “kindling” hypothesis.
      ), and this effect could be mediated by cumulative epigenetic changes induced by repetitive stressor exposure.
      These hypotheses can be evaluated only by longitudinal studies. To date, there are few such studies in PTSD. In a study assessing epigenetic markers in veterans before and after deployment, differential changes in DNA methylation of the IL18 and H19 loci and repetitive genomic elements were observed in veterans exposed to trauma who developed PTSD versus veterans exposed to trauma who did not develop the disorder (
      • Rusiecki J.A.
      • Byrne C.
      • Galdzicki Z.
      • Srikantan V.
      • Chen L.
      • Poulin M.
      • et al.
      PTSD and DNA methylation in select immune function gene promoter regions: A repeated measures case-control study of U.S. military service members.
      ). Another study assessing epigenetic markers as predictors of response to prolonged exposure psychotherapy noted that pretreatment methylation levels of the NR3C1 exon 1F predicted PTSD responses, and changes in methylation of the FKBP5 promoter occurred concomitantly with recovery from the disorder (
      • Yehuda R.
      • Daskalakis N.P.
      • Lehrner A.
      • Desarnaud F.
      • Bader H.N.
      • Makotkine I.
      • et al.
      Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring.
      ). These data suggest that methylation changes may be dynamic, occur concomitantly with development or recovery from PTSD, and may be useful as biomarkers to track the course of the disorder.

      Limitations of Epigenetic Studies in PTSD AND FUTURE DIRECTIONS

      An increasing body of evidence supports a role for epigenetic regulation in PTSD. Although these findings offer an exciting prospect for future research endeavors, several limitations of epigenetic studies in PTSD should be highlighted. First, most studies to date use either animal models or blood tissue in humans. These studies are inherently limited by the tissue specificity of epigenetic changes and the inability to interrogate brain tissue in living humans. This shortcoming may be overcome to some extent by translational approaches that combine data from animal models, postmortem human brain tissue, and peripheral blood assessments in living humans. Such studies may provide converging evidence for epigenetic signatures that are common in peripheral blood and analogous brain regions in animals and humans. Some studies that have translated evidence across animals and humans suggest that epigenetic changes for certain genetic loci may be observed in brain and periphery (
      • Provencal N.
      • Suderman M.J.
      • Guillemin C.
      • Massart R.
      • Ruggiero A.
      • Wang D.
      • et al.
      The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells.
      ,
      • Ressler K.J.
      • Mercer K.B.
      • Bradley B.
      • Jovanovic T.
      • Mahan A.
      • Kerley K.
      • et al.
      Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.
      ). Second, although epigenetic regulation of some genomic sites in PTSD, such as the 1F promoter of the NR3C1 gene, have been corroborated by multiple studies in PTSD, replication of existing epigenetic findings is largely lacking and should be sought by future studies. Even for the most replicated finding to date concerning the 1F promoter of the NR3C1 gene, controversial results have been reported; for example, although 89% of the studies exploring the GR exon variant 1F in humans found increased methylation with early life adversity, only 17% of the studies relating the methylation of this site to stress responsivity and psychopathology found the same direction of effects (
      • Turecki G.
      • Meaney M.J.
      Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review [published online ahead of print Dec 13].
      ). Another limitation is imposed by the current diagnostic definition of PTSD, which is phenomenologic and dichotomous. Future studies could benefit by examining outcomes based on carefully selected endophenotypes or dimensional phenotypes. In addition, although studies on the epigenetics of PTSD to date have focused on DNA methylation, it is important to consider the full spectrum of epigenetic modifications that have been implicated in the pathogenesis of psychiatric disorders, including posttranslational histone modifications, noncoding RNAs, and three-dimensional changes in chromatin conformation (
      • Jakovcevski M.
      • Akbarian S.
      Epigenetic mechanisms in neurological disease.
      ,
      • Bharadwaj R.
      • Peter C.J.
      • Jiang Y.
      • Roussos P.
      • Vogel-Ciernia A.
      • Shen E.Y.
      • et al.
      Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition.
      ). Because these epigenetic processes may act in concert to regulate gene function (
      • Murr R.
      Interplay between different epigenetic modifications and mechanisms.
      ), studies examining the interplay among various epigenetic mechanisms could offer a more comprehensive understanding of epigenetic regulation in PTSD. Lastly, efforts should be made to identify epigenetic changes that mediate positive outcomes after trauma exposure, such as posttraumatic growth. Mimicking these changes to promote resilience to trauma would be a desirable effect of preventive strategies for PTSD.

      Conclusions

      Beyond their value in promoting mechanistic understanding and use as disease biomarkers, epigenetic modifications are potentially reversible and represent attractive candidates for the development of new treatments for psychiatric disorders. Studies in rodents have used epigenetic drugs successfully to target DNA methyltransferases or histone-modifying enzymes (
      • Zovkic I.B.
      • Sweatt J.D.
      Epigenetic mechanisms in learned fear: Implications for PTSD.
      ,
      • Kwapis J.L.
      • Wood M.A.
      Epigenetic mechanisms in fear conditioning: Implications for treating post-traumatic stress disorder.
      ). Such manipulations showed that DNA methylation and histone acetylation are involved in every step of fear memory, from the initial consolidation to extinction and long-term potentiation, processes that have been shown to be altered in patients with PTSD. Pharmaceutical inhibition of histone deacetylation also was shown to reverse the deleterious effect of early life adversity in rats (
      • Klengel T.
      • Mehta D.
      • Anacker C.
      • Rex-Haffner M.
      • Pruessner J.C.
      • Pariante C.M.
      • et al.
      Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.
      ), further supporting the potential utility of epigenetic drugs in the treatment and prevention of trauma-related pathologies. Although the road to safe and effective clinical use of epigenetic drugs is still long, it is hoped that elucidating epigenetic mechanisms of PTSD may improve available treatments for this disorder.

      Acknowledgments and Disclosures

      This work was supported by a European Research Council starting grant (Grant No. 281338, Gene x environment interactions in affective disorders - elucidating molecular mechanisms GxE molmech).
      The authors report no biomedical financial interests or potential conflicts of interest.

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