FKBP5 and attention bias for threat

2013

Context: The FKBP5 gene product regulates glucocorticoid receptor (GR) sensitivity and hypothalamicpituitary-adrenal axis functioning, and has been associated with a number of stress-related psychiatric disorders. The study of intermediate phenotypes, such as emotion-processing biases and their neural substrates, provides a way to clarify the mechanisms by which FKBP5 dysregulation mediates psychopathology risk. Objective: To examine whether allelic variations for a putatively functional SNP associated with FKBP5 gene regulation (rs1360780) would relate differentially to attentional bias for threat; this was measured through behavioral response on a dot probe task and hippocampal activation during task performance. Morphological substrates of differential hippocampal response were also measured. Design: Cross-sectional study examining associations between genotype, behavioral response and neural response (using fMRI) on the dot probe; Voxel-based morphometry (VBM), global and local shape analyses were used to measure structural differences in hippocampi between genotype groups. Setting: Participants were recruited from primary care clinics of a publicly-funded hospital in Atlanta, Georgia. Participants: An African-American cohort (N=103), separated into two groups by genotype: one genotype group included carriers of the rs1360780 'T' allele, which has been previously associated with increased risk for PTSD and affective disorders; the other group did not carry this allele. Behavioral data included both genders (N=103); the MRI cohort (n=36) included only females. Main Outcome Measures: Behavioral and fMRI (BOLD) response, VBM and shape analyses Results: Carriers of the rs1360780 'T' allele showed an attention bias towards threat, compared to individuals without this allele. Carriers of this allele demonstrated corresponding increases in hippocampal activation and differences in morphology; global and local shape analyses revealed alterations in hippocampal shape, for TT/TC, versus CC genotype groups. Conclusions: Genetic variants of FKBP5 may be associated with risk for stress-related psychopathology via differential effects on hippocampal structure and function, resulting in altered attentional response to perceived threat.

Journal of Psychiatric Research, 2014

FK506 binding protein 5 (FKBP5) is induced by stress and regulates glucocorticoid receptor sensitivity. The T allele of the single nucleotide polymorphism (SNP) FKBP5 rs1360780 (C/T) is associated with an increased risk of post-traumatic stress disorder (PTSD) and reduced hippocampal volume in traumatized or depressed subjects. To examine whether this SNP affects brain structures that regulate stress response, we obtained magnetic resonance imaging data of the brain in 162 healthy subjects using a 1.5 T system. Gray matter volumes and diffusion tensor imaging data were compared between individuals with and without the T allele, using optimized voxel-based morphometry. We found that the dorsal anterior cingulate cortex (dACC) volume was smaller in T carriers than in non-T carriers (P < 0.001). T carriers also showed significantly higher mean diffusivity values in the dACC and posterior cingulate cortex (PCC) compared with non-T carriers (P < 0.001). Our results suggest that carrying the T allele of FKBP5 rs1360780 is associated with smaller gray matter volumes in the dACC and altered white matter integrity in the dACC and PCC in the non-clinical population, which might constitute the structural basis of stressrelated psychiatric disorders including PTSD.

Brain Structure and Function, 2014

Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective selfreport (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. The present results point to a functional involvement of FKBP5 in intermediate phenotypes associated with emotional processing, suggesting a possible mechanism for this gene in conferring susceptibility to stress-related disorders.

Psychoneuroendocrinology, 2016

The gene that encodes the FK506-binding protein 5 (FKBP5) is regarded as a candidate for investigating how negative life events interact with a genetic predisposition to stress-related disorders, such as depression and anxiety. Given the role of FKBP5 as an important regulator of stress responses, we aimed to investigate if single-nucleotide polymorphisms (SNPs) in FKBP5-in the presence/absence of exposure to violence-are associated with symptoms of depression and anxiety. Data from two community-based samples of adolescents (n = 1705) and young adults (n = 1800) regarding ratings on depression, anxiety, exposure to violence and FKBP5 genotype were collected. A risk haplogenotype including the minor alleles of seven common SNPs in the FKBP5 (rs3800373, rs9296158, rs7748266, rs1360780, rs9394309, rs9470080 and rs4713916) conferred higher ratings on anxiety among females, but not males, in the presence of violence. Exposure to violence and female sex were associated with higher ratings on both depression and anxiety, with the exception of ratings on depression among young adults, on which sex had no effect. Ratings on depression were not associated with the haplogenotype. These findings may correspond to differences in the regulation of the HPA axis and with the higher vulnerability to anxiety in females.

Psychological Medicine, 2015

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2015

Exposure to stress during critical periods of development can have adverse effects on adult health behaviors, and genetic vulnerabilities may enhance these stress effects. We carried out an exploratory examination of the interaction of early-life adversity (ELA) and FKBP5 genotypes, AA/AG vs GG (rs9296158) polymorphisms, on psychological, physiological, and behavioral characteristics of 252 healthy young adults, 18-25 years of age. FKBP5 contributes to the conformation and functional status of the glucocorticoid receptor (GR). Its expression is upregulated by cortisol exposure during stressful episodes, with greater upregulation in A-allele carriers. As such, FKBP5 expression and GR function in A-allele carriers may be environmentally sensitive and suitable for study of gene-by-environment (G × E) effects. Compared to FKBP5, GG homozygotes (N=118), healthy young-adult AA/AG carriers (N=132) lacking psychiatric morbidity had progressively worse performance on the Stroop color-word ta...

Journal of Affective Disorders, 2017

Background-Gene-environment interaction contributes to the risks of psychiatric disorders. Interactions between FKBP5 gene variants and early-life stress may enhance the risk not only for mood disorder, but also for a number of other behavioral phenotypes. The aim of the present study was to review and conduct a meta-analysis on the results from published studies examining interaction between FKBP5 gene variants and early-life stress and their associations with stressrelated disorders such as major depression and PTSD. Methods-A literature search was conducted using PsychINFO and PubMed databases until May 2017. A total of 14 studies with a pooled total of 15109 participants met the inclusion criteria, the results of which were combined and a meta-analysis was performed using the differences in correlations as the effect measure. Based on literature, rs1360780, rs3800373, and rs9470080 SNPs were selected within the FKBP5 gene and systematic review was conducted. Results-Based on the Comprehensive Meta-Analysis software, no publication bias was detected. Sensitivity analysis and credibility of meta-analysis results also indicated that the analyses were stable. The meta-analysis showed that individuals who carry T allele of rs1360780, C-allele of rs3800373 or T-allele of rs9470080 exposed to early-life trauma had higher risks for depression or PTSD. Limitations-The effects of ethnicity, age, sex, and different stress measures were not examined due to limited sample size. Conclusions-These results provide strong evidence of interactions between FKBP5 genotypes and early-life stress, which could pose a significant risk factor for stress-associated disorders such as major depression and PTSD.

Depression and Anxiety, 2013

Anxiety 30:1170-1176, 2013. C 2013 Wiley Periodicals, Inc.

Neuropsychopharmacology, 2011

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; 95% CI ¼ 0.64-33.7; 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.

Translational Psychiatry, 2014

Exposure-based therapies are considered the state-of-the-art treatment for Posttraumatic Stress Disorder (PTSD). Yet, a substantial number of PTSD patients do not recover after therapy. In the light of the well-known gene × environment interactions on the risk for PTSD, research on individual genetic factors that influence treatment success is warranted. The gene encoding FK506-binding protein 51 (FKBP5), a co-chaperone of the glucocorticoid receptor (GR), has been associated with stress reactivity and PTSD risk. As FKBP5 single-nucleotide polymorphism rs1360780 has a putative functional role in the regulation of FKBP5 expression and GR sensitivity, we hypothesized that this polymorphism influences PTSD treatment success. We investigated the effects of FKBP5 rs1360780 genotype on Narrative Exposure Therapy (NET) outcome, an exposure-based short-term therapy, in a sample of 43 survivors of the rebel war in Northern Uganda. PTSD symptom severity was assessed before and 4 and 10 months after treatment completion. At the 4-month follow-up, there were no genotype-dependent differences in therapy outcome. However, the FKBP5 genotype significantly moderated the long-term effectiveness of exposure-based psychotherapy. At the 10-month follow-up, carriers of the rs1360780 risk (T) allele were at increased risk of symptom relapse, whereas non-carriers showed continuous symptom reduction. This effect was reflected in a weaker treatment effect size (Cohen's D = 1.23) in risk allele carriers compared with non-carriers (Cohen's D = 3.72). Genetic factors involved in stress response regulation seem to not only influence PTSD risk but also responsiveness to psychotherapy and could hence represent valuable targets for accompanying medication.