Interaction Between <emph type="ital">FKBP5</emph> and Childhood Trauma and Risk of Aggressive Behavior

Abstract

Context Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamicpituitary-adrenal axis dysregulation. Objective To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior. Design Cross-sectional study. Four FKBP5 single-nucleotide polymorphisms used in previous studies (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. Three diplotypes were derived from 2 major putatively functional haplotypes regulating protein expression that were previously associated with glucocorticoid receptor sensitivity. Setting Penitentiary District of Abruzzo-Molise in central Italy. Participants A population of 583 male Italian prisoners recruited between 2005 and 2008. Main Outcome Measures A comprehensive analysis of aggression and impulsivity was undertaken using the Brown-Goodwin Lifetime History of Aggression (BGHA) questionnaire, the Buss-Durkee Hostility Inventory (BDHI), and the Barratt Impulsiveness Scale (BIS). A history of childhood trauma was investigated with the Childhood Trauma Questionnaire. The interaction between the FKBP5 diplotypes and childhood trauma on measures of aggression was analyzed. Analyses were replicated with a second behavioral measure of aggression: violent behavior in jail. Individual single-nucleotide polymorphism analysis was performed. Results Childhood trauma had a significant effect on BGHA and BDHI scores but not on BIS scores. We observed a significant influence of the FKBP5 high-expression diplotype on both a lifetime history of aggressive behavior (BGHA) (P = .012) and violent behavior in jail (P = .025) but only in individuals exposed to childhood trauma, in particular to physical abuse. No main effect of the FKBP5 diplotypes was observed. Conclusion These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior.

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

“…Second, it is not clear whether the associations between FKBP5 SNPs and withdrawal severity may be attributed to other comorbid psychiatric disorders, such as major depression or PTSD. In addition, childhood trauma has been shown to interact with FKBP5 gene variation to influence the stress response (Binder et al, 2008;Roy et al, 2010;Xie et al, 2010;Bevilacqua et al, 2012) and is considered to be a confounding variable in HPA axis dysregulation in alcohol-dependent patients (Schafer et al, 2010). Therefore, we were unable to exclude the contribution from stressful life events to our results.…”

“…In addition, the minor alleles of rs9470080 and rs1360780 are associated with total cortisol secretion during the day expressed as the AUC (cortisol AUC ) (Velders et al, 2011). Finally, a haplotype of the above-listed SNPs has been associated with suicidal attempts (Roy et al, 2010) or aggressive behavior (Bevilacqua et al, 2012) among individuals with childhood trauma.…”

“…The functional association between FKBP5 gene variants and HPA axis regulation appears to be altered, for example, the high expression alleles may instead be associated with increased GR sensitivity, in the presence of disease where feedback inhibition has been impaired along with activation of the HPA axis (Binder et al, 2004;Bevilacqua et al, 2012). Such is the case in subjects with depression or PTSD, in whom the high expression alleles are associated with greater glucocorticoid sensitivity, compared with controls where they are associated with increased glucocorticoid resistance ( Binder et al, 2004Binder et al, , 2008Bevilacqua et al, 2012).…”

“…Such is the case in subjects with depression or PTSD, in whom the high expression alleles are associated with greater glucocorticoid sensitivity, compared with controls where they are associated with increased glucocorticoid resistance ( Binder et al, 2004Binder et al, , 2008Bevilacqua et al, 2012). Binder et al (2004Binder et al ( , 2009 suggest that the high expression alleles of the FKBP5 gene may counteract depression-related HPA axis hyperactivity via compensatory mechanisms, allowing a faster restoration of normal HPA axis function and a more rapid response to antidepressants in depressed individuals.…”

Stress and the social brain: behavioural effects and neurobiological mechanisms

“…Further support for this notion was provided by a study which showed that activation of GRs in dopamine receptor-expressing neurons in mesocorticolimbic and striatal circuits promoted social aversion induced by a subchronic social defeat procedure in mice 75 . Moreover, in humans, an interaction between genetic variation in the gene encoding FKBP5 (a cochaperone of heat shock protein 90 that affects the transcriptional capacity of GRs) and childhood trauma influences both lifetime history of aggressive behavior 76 and the glucocorticoid response to stress 77 . These findings suggest that individual differences in the neurodevelopmental trajectories leading to antisociality might be related to genetic variation in HPA-axis-related genes that affect the functioning of the stress systems during development and its consequent promotion of long-lasting epigenetic adaptations 76,78 .…”