Association of &lt;emph type="ital"&gt;FKBP5&lt;/emph&gt; Polymorphisms and Childhood Abuse With Risk of Posttraumatic Stress Disorder Symptoms in Adults

Binder, Elisabeth B.; Bradley, Rebekah; Liu, Wei; Epstein, Michael P.; Deveau, Todd C.; Mercer, Kristina B.; Tang, Yi-Lang; Gillespie, Charles F.; Heim, Christine; Nemeroff, Charles B.; Schwartz, Ann C.; Cubells, Joseph F.; Ressler, Kerry J.

doi:10.1001/jama.299.11.1291

Cited by 1,207 publications

(1,094 citation statements)

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“…However, the true value of a TT genotype screening in exposed subjects should be assessed longitudinally. It is noteworthy that our results are in line with previous studies, associating the high-induction T allele of rs1360780 with an altered cortisol response to experimental stress (Luijk et al, 2010;Ising et al, 2008), with faster response to antidepressant treatment (Binder et al, 2004) and with the susceptibility to PTSD after childhood maltreatment (Xie et al, 2010;Binder et al, 2008). According to the pathophysiological model, the high-induction alleles of the FKBP5 gene are associated with a relative GR resistance Binder, 2009), which could facilitate a long-lasting dysregulation of the HPA axis after childhood abuse and thereby increasing the risk for MDD.…”

Section: Figuresupporting

confidence: 92%

“…Following the approach of gene-environment interactions (Caspi et al, 2003;Grabe et al, 2005Grabe et al, , 2011, Binder et al (2008) investigated the interaction between SNPs of the FKBP5 gene and childhood abuse in adult posttraumatic stress disorder (PTSD). They found four highly linked SNPs of the FKBP5 gene (including rs1360780) that interacted significantly with childhood abuse to predict PTSD but not depression scores in adulthood.…”

Section: Introductionmentioning

confidence: 99%

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Moderation of Adult Depression by a Polymorphism in the FKBP5 Gene and Childhood Physical Abuse in the General Population

Appel

Schwahn

Mahler

et al. 2011

Neuropsychopharmacol

208

149

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Childhood maltreatment and depressive disorders have both been associated with a dysregulation of the hypothalamic-pituitary-adrenal axis. The FKBP5 gene codes for a co-chaperone regulating the glucocorticoid-receptor sensitivity. Previous evidence suggests that subjects carrying the TT genotype of the FKBP5 gene single-nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to adverse effects of experimental stress. We therefore tested the hypothesis of an interaction of childhood abuse with rs1360780 in predicting adult depression. In all, 2157 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and Childhood Trauma Questionnaire. The DSM-IV diagnosis of major depressive disorder (MDD) was assessed by interview. Genotypes of rs1360780 were taken from the Affymetrix Human SNP Array 6.0. Significant interaction (p ¼ 0.006) of physical abuse with the TT genotype of rs1360780 was found increasing the BDI-II score to 17.4 (95% confidence interval (CI) ¼ 12.0-22.9) compared with 10.0 (8.2-11.7) in exposed CC/CT carriers. Likewise, the adjusted odds ratio for MDD in exposed TT carriers was 8.2 (95% CI ¼ 1.9-35.0) compared with 1.3 (0.8-2.3) in exposed subjects with CC/CT genotypes. Relative excess risk due to interaction (RERI) analyses confirmed a significant additive interaction effect (RERI ¼ 6.8; po0.05). In explorative analyses, the most severe degree of sexual and emotional abuse also yielded significant interaction effects (po0.05). This study revealed interactions between physical abuse and rs1360780 of the FKBP5 gene, confirming its role in the individual susceptibility to depression. Given the large effect sizes, rs1360780 could be included into prediction models for depression in individuals exposed to childhood abuse.

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Section: Figuresupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Moderation of Adult Depression by a Polymorphism in the FKBP5 Gene and Childhood Physical Abuse in the General Population

Appel

Schwahn

Mahler

et al. 2011

Neuropsychopharmacol

208

149

View full text Add to dashboard Cite

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“…Interestingly, epigenetic modifications of FKBP5 (and subsequently GR activity) have been found in psychiatric illness, including PTSD (Binder, 2009;Maddox et al, 2013). Furthermore, FKBP5 single nucleotide polymorphisms (SNPs) have been associated with more rapid feedback and enhanced HPA axis suppression using the dexamethasone (Dex; GR receptor agonist) suppression test (Binder et al, 2008;Klengel et al, 2013). This observation is consistent with differential FKBP5 regulation as a potential intermediate phenotype for trauma-and stress-related disorders.…”

Section: Introductionmentioning

confidence: 73%

“…Four SNPs of the FKBP5 gene (rs9296158, rs3800373, rs1360780, and rs9470080) were found to interact with severity of child abuse as predictors of adult PTSD symptoms in urban, previously traumatized civilians (Binder et al, 2008). Additionally, it was found that the rs1360780 SNP moderates the risk for PTSD after early trauma and DNA methylation within functional glucocorticoid response elements of the FKBP5 gene (Klengel et al, 2013).…”

Section: Introductionmentioning

confidence: 95%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shockmediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

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“…Specifically, early life trauma is associated with impairment in cognitive and emotional functions (Burri, Maercker, Krammer, & Simmen-Janevska, 2013; Pechtel & Pizzagalli, 2011) across studies exploring genetic (Klengel et al, 2013), psychosocial (Ogle, Rubin, & Siegler, 2013), and gene by environmental contributions (Binder et al, 2008). Early life trauma was not evaluated in this work, thereby limiting our ability to address a potential source of cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

Evaluating web-based cognitive-affective remediation in recent trauma survivors: study rationale and protocol

Fine

Achituv

Etkin

et al. 2018

European Journal of Psychotraumatology

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Background: The immediate aftermath of traumatic events is a period of enhanced neural plasticity, following which some survivors remain with post-traumatic stress disorder (PTSD) whereas others recover. Evidence points to impairments in emotional reactivity, emotion regulation, and broader executive functions as critically contributing to PTSD. Emerging evidence further suggests that the neural mechanisms underlying these functions remain plastic in adulthood and that targeted retraining of these systems may enhance their efficiency and could reduce the likelihood of developing PTSD. Administering targeted neurocognitive training shortly after trauma exposure is a daunting challenge. This work describes a study design addressing that challenge. The study evaluated the direct effects of cognitive remediation training on neurocognitive mechanisms that hypothetically underlay PTSD, and the indirect effect of this intervention on emerging PTSD symptoms. Method: We describe a study rationale, design, and methodological choices involving: (a) participants’ enrolment; (b) implementation and management of a daily self-administered, web-based intervention; (c) reliable, timely screening and assessment of treatment of eligible survivors; and (d) defining control conditions and outcome measures. We outline the rationale of choices made regarding study sample, timing of intervention, measurements, monitoring participants’ adherence, and ways to harmonize and retain interviewers’ fidelity and mitigate eventual burnout by repeated contacts with recently traumatized survivors. Conclusion: Early web-based interventions targeting causative mechanisms of PTSD can be informed by the model presented in this paper.

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Association of <emph type="ital">FKBP5</emph> Polymorphisms and Childhood Abuse With Risk of Posttraumatic Stress Disorder Symptoms in Adults

Cited by 1,207 publications

References 86 publications

Moderation of Adult Depression by a Polymorphism in the FKBP5 Gene and Childhood Physical Abuse in the General Population

Moderation of Adult Depression by a Polymorphism in the FKBP5 Gene and Childhood Physical Abuse in the General Population

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Evaluating web-based cognitive-affective remediation in recent trauma survivors: study rationale and protocol

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