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FKBP5 genotype-dependent DNA methylation and mRNA regulation after psychosocial stress in remitted depression and healthy controls.

ABSTRACT: Polymorphisms in the FK506 binding protein 5 (FKBP5) gene have been shown to influence glucocorticoid receptor sensitivity, stress response regulation, and depression risk in traumatized subjects, with most consistent findings reported for the functional variant rs1360780. In the present study, we investigated whether the FKBP5 polymorphism rs1360780 and lifetime history of major depression are associated with DNA methylation and FKBP5 gene expression after psychosocial stress.A total of 116 individuals with a positive (n = 61) and negative (n = 55) lifetime history of major depression participated in the Trier Social Stress Test. We assessed plasma cortisol concentrations, FKBP5 mRNA expression, and CpG methylation of FKBP5 intron 7 in peripheral blood cells.Genotype-dependent plasma cortisol response to psychosocial stress exposure was observed in healthy controls, with the highest and longest-lasting cortisol increase in subjects with the TT genotype of the FKBP5 polymorphism rs1360780, and healthy controls carrying the T risk allele responded with a blunted FKBP5 mRNA expression after psychosocial stress. No genotype effects could be found in remitted depression.The FKBP5 rs1360780 polymorphism is associated with plasma cortisol and FKBP5 mRNA expression after psychosocial stress in healthy controls but not in remitted depression. Preliminary results of the DNA methylation analysis suggest that epigenetic modifications could be involved.

SUBMITTER: Hohne N

PROVIDER: S-EPMC4360217 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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FKBP5 genotype-dependent DNA methylation and mRNA regulation after psychosocial stress in remitted depression and healthy controls.

Höhne Nina N Poidinger Maximilian M Merz Franziska F Pfister Hildegard H Brückl Tanja T Zimmermann Petra P Uhr Manfred M Holsboer Florian F Ising Marcus M

The international journal of neuropsychopharmacology 20141213 4

<h4>Background</h4>Polymorphisms in the FK506 binding protein 5 (FKBP5) gene have been shown to influence glucocorticoid receptor sensitivity, stress response regulation, and depression risk in traumatized subjects, with most consistent findings reported for the functional variant rs1360780. In the present study, we investigated whether the FKBP5 polymorphism rs1360780 and lifetime history of major depression are associated with DNA methylation and FKBP5 gene expression after psychosocial stress ...[more]

PMID: 25522420

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Project description:The recurrent nature of Major Depressive Disorder (MDD) necessitates a better understanding of mechanisms facilitating relapse. MDD has often been associated with abnormal emotion regulation, underpinned by aberrant interactions between the prefrontal cortex and subcortical areas. We assessed whether neural regulation abnormalities remain after remission and relate to emotion regulation problems in daily life. At the baseline measurement of a randomized controlled trial, an emotion regulation task was performed during fMRI scanning by 46 remitted recurrent (rrMDD) patients and 24 healthy controls. We assessed both fMRI peak activity and the temporal dynamics of the neural response during passive attendance and explicit regulation of positive and negative emotions. Furthermore, we assessed regulation strategy use in daily life using questionnaires, and attentional biases using a modified attentional dot-probe task. RrMDD patients showed lower activation and different temporal dynamics in occipital, parietal, and prefrontal brain regions during passive attendance of emotional material compared to healthy controls. During explicit downregulation of negative emotions, no group differences were found. However, during explicit upregulation of positive emotions, rrMDD patients showed a different neural response over time in the insula. Behaviourally, rrMDD patients were characterized by dysfunctional regulation strategies in daily life. Within rrMDD patients, rumination was associated with activation within a limbic- prefrontal network. After remission, immediate emotional processing seems unaffected, but regulatory abnormalities remain, especially uninstructed and in daily life. Abnormal insula activation during positive upregulation suggests decreased monitoring of positive emotions. The relation between inadequate rumination and brain activity during emotion regulation suggests that regulation of both positive and negative affect is important in understanding neurocognitive underpinnings of resilience.

Project description:Background: Major Depressive Disorder (MDD) is a highly prevalent, recurrent, and potentially chronic disorder. Identifying risk factors and underlying mechanisms to inform preventive and therapeutic interventions is therefore imperative. Emotion regulation is a proposed factor in the development and maintenance of MDD. The aim of the present review was to summarize and synthesize research on self-reported emotion regulation strategy use and emotion regulation abilities in adults diagnosed with current and remitted MDD. Methods: Seventy-two eligible studies were retrieved from databases through a systematic literature search. Group differences between individuals with current MDD, remitted MDD, and healthy controls were calculated using meta-analytic procedures. Meta-regression analyses investigated potential moderator effects on emotion regulation difficulties. Results: Results indicated that individuals with current MDD report higher maladaptive emotion regulation strategy use for avoidance (Hedges' g = 1.3), rumination (g = 2.1), and suppression (g = 1.1) compared to healthy controls. Also, they reported lower adaptive emotion regulation strategy use for acceptance (g = -1.0), problem solving (g = -1.0), and reappraisal (g = -0.7). Individuals with current MDD reported limited general emotion regulation abilities, indicated by higher alexithymia (g = 1.45), lower emotional awareness (g = -0.95), emotional clarity (g = -1.50) and emotional tolerance (g = -1.89). Similar results were found in individuals with remitted MDD for avoidance (g = 1.0), rumination (g = 1.1), suppression (g = 0.6), and general emotion regulation abilities. However, no difference was found between individuals with remitted MDD and healthy controls for adaptive emotion regulation strategies. Meta-regression analyses suggest that age of illness onset, comorbid anxiety and duration of remission influence emotion regulation. Conclusion: The present review and meta-analysis indicates that individuals with current and remitted MDD have difficulties with emotion regulation compared to individuals who have never been depressed. Although depressive symptoms improve, emotion regulation difficulties may continue, and could be a contributing factor to relapse. Our findings inform future research on emotion regulation and psychotherapeutic interventions.

Dataset Information

FKBP5 genotype-dependent DNA methylation and mRNA regulation after psychosocial stress in remitted depression and healthy controls.

Publications

FKBP5 genotype-dependent DNA methylation and mRNA regulation after psychosocial stress in remitted depression and healthy controls.

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