Using Polymorphisms in FKBP5 to Define Biologically Distinct Subtypes of Posttraumatic Stress Disorder

Mehta, Divya; Gonik, Mariya; Klengel, Torsten; Rex‐Haffner, Monika; Menke, Andreas; Rubel, Jennifer; Mercer, Kristina B.; Pütz, Benno; Bradley, Bekh; Holsboer, Florian; Ressler, Kerry J.; Müller‐Myhsok, Bertram; Binder, Elisabeth B.

doi:10.1001/archgenpsychiatry.2011.50

Cited by 186 publications

(140 citation statements)

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“…As all SNPs showed a low frequency of the homozygous risk allele genotype, polymorphisms were coded to reflect a dominant model, with homozygotes of the “non‐risk” allele versus “risk” allele carriers. This is in accordance with previous studies of response to environmental stimuli and psychiatric outcomes 32, 41 and interactions between genotype and DNA methylation 11…”

Section: Analysessupporting

confidence: 93%

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

et al. 2015

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BackgroundHypothalamic–pituitary–adrenal (HPA) axis functioning has been implicated in the development of stress‐related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT).MethodsChildren with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response).ResultsTreatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response.ConclusionsAllele‐specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype‐dependent manner.

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Section: Analysessupporting

confidence: 93%

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

et al. 2015

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“…Microarray gene-expression results had been reported in a previous report (34) for a subset of these patients (n = 211). For this study, we selected patients from a now expanded set of microarray gene-expression results (adding 185 new samples with gene-expression arrays to the previously reported ones) and we have now also added DNA methylation array data for all 396 individuals.…”

Section: Methodsmentioning

confidence: 64%

“…The 396 participants were selected from a larger study, which has been described previously (34). Microarray gene-expression results had been reported in a previous report (34) for a subset of these patients (n = 211).…”

Section: Methodsmentioning

confidence: 99%

Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder

Mehta

Klengel

Conneely³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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486

348

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Childhood maltreatment is likely to influence fundamental biological processes and engrave long-lasting epigenetic marks, leading to adverse health outcomes in adulthood. We aimed to elucidate the impact of different early environment on disease-related genomewide gene expression and DNA methylation in peripheral blood cells in patients with posttraumatic stress disorder (PTSD). Compared with the same trauma-exposed controls (n = 108), geneexpression profiles of PTSD patients with similar clinical symptoms and matched adult trauma exposure but different childhood adverse events (n = 32 and 29) were almost completely nonoverlapping (98%). These differences on the level of individual transcripts were paralleled by the enrichment of several distinct biological networks between the groups. Moreover, these gene-expression changes were accompanied and likely mediated by changes in DNA methylation in the same loci to a much larger proportion in the childhood abuse (69%) vs. the non-child abuse-only group (34%). This study is unique in providing genome-wide evidence of distinct biological modifications in PTSD in the presence or absence of exposure to childhood abuse. The findings that nonoverlapping biological pathways seem to be affected in the two PTSD groups and that changes in DNA methylation appear to have a much greater impact in the childhood-abuse group might reflect differences in the pathophysiology of PTSD, in dependence of exposure to childhood maltreatment. These results contribute to a better understanding of the extent of influence of differences in trauma exposure on pathophysiological processes in stress-related psychiatric disorders and may have implications for personalized medicine.hildhood maltreatment is a complex problem that exerts an enormous impact on individuals, families, and society, and is of great significance for public health. Maltreatment during childhood likely influences fundamental biological processes and engraves long-lasting epigenetic marks, leading to adverse health outcomes in adulthood (1). Exposure to adverse life events in childhood has not only been linked to an increased susceptibility for a number of psychiatric disorders, but also to cardiovascular disease, diabetes, and chronic lung disease, possibly via long-term influences on the immune system (2-9). This finding suggests that early adverse experiences not only alter neurobiological systems leading to an increased risk for psychiatric disorders, but may have a long-lasting effect on a number of organ systems. Experience of childhood abuse might influence these biological systems via epigenetic modifications conferring lifelong susceptibility to disease. In fact, in humans, distinct epigenetic and gene-expression changes have been observed in postmortem brains of suicide victims with a history of childhood abuse compared with suicide victims without a history of childhood abuse or control subjects (10).Early life trauma is a strong risk factor for stress-related psychiatric disorders, which themselves have been shown ...

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“…Nuclear factor-κB (NFκB), signal transducer and activator of transcription 5B, and nuclear factor I/A are all critical transcription factors with substantive roles in the activation of cytokine responses to challenge whose activity is increased in the presence of PTSD (Guardado et al, 2016;O'Donovan et al, 2011;Pace et al, 2012;Sarapas et al, 2011). Gene expression of the proinflammatory cytokine IL-18 and its receptor IL-18R1 is decreased in individuals with PTSD (Mehta et al, 2011;Segman et al, 2005;Zieker et al, 2007). This decrease in IL-18 gene expression is consistent with epigenetic findings indicating that increased methylation in the promoter region of IL-18 is associated with the development of PTSD in soldiers following military deployment (Rusiecki et al, 2013).…”

Section: Ptsd and Inflammationmentioning

confidence: 99%

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

Michopoulos

Powers

Gillespie

et al. 2016

Neuropsychopharmacol

544

376

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The study of inflammation in fear-and anxiety-based disorders has gained interest as growing literature indicates that proinflammatory markers can directly modulate affective behavior. Indeed, heightened concentrations of inflammatory signals, including cytokines and C-reactive protein, have been described in posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and phobias (agoraphobia, social phobia, etc.). However, not all reports indicate a positive association between inflammation and fear-and anxiety-based symptoms, suggesting that other factors are important in future assessments of inflammation's role in the maintenance of these disorders (ie, sex, co-morbid conditions, types of trauma exposure, and behavioral sources of inflammation). The most parsimonious explanation of increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines. Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus). Taken together, the available data suggest that targeting inflammation may serve as a potential therapeutic target for treating these fear-and anxiety-based disorders in the future. However, the field must continue to characterize the specific role pro-inflammatory signaling in the maintenance of these unique psychiatric conditions.

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Using Polymorphisms in FKBP5 to Define Biologically Distinct Subtypes of Posttraumatic Stress Disorder

Cited by 186 publications

References 53 publications

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

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