Interaction Between FKBP5 and Childhood Trauma and Risk of Aggressive Behavior

LNG/NIAAA, NIH, Rockville, MD 20852, USA.
Archives of general psychiatry (Impact Factor: 14.48). 01/2012; 69(1):62-70. DOI: 10.1001/archgenpsychiatry.2011.152
Source: PubMed


Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamic-pituitary-adrenal axis dysregulation.
To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior.
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.
Penitentiary District of Abruzzo-Molise in central Italy.
A population of 583 male Italian prisoners recruited between 2005 and 2008.
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.
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.
These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior.

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    • "The relevance of these genetic variations for stressrelated psychopathology is thus well established. For example, a number of studies demonstrate significant interactions between childhood adversity and single nucleotide polymorphisms (SNPs) of the FKBP5 gene (most commonly rs1360870) affecting a range of psychopathologies, including posttraumatic stress disorder (Binder et al., 2008; Xie et al., 2010), depression (Appel et al., 2011; Zimmermann et al., 2011), suicide risk (Roy et al., 2010), aggression (Bevilacqua et al., 2012) and psychosis (Collip et al., 2013). This SNP has also been associated with biased attention toward threat and associated hippocampal function and structure (Fani et al., 2013), and neurophysiology of the cingulum (Fani et al., 2013). "
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    ABSTRACT: Common variants of the FK506 binding protein 5 (FKBP5) gene are implicated in psychotic and other disorders, via their role in regulating glucocorticoid receptor (GR) receptor sensitivity and effects on the broader function of the HPA system in response to stress. In this study, the effects of four FKBP5 polymorphisms (rs1360780, rs9470080, rs4713902, rs9394309) on IQ and eight other cognitive domains were examined in the context of exposure to childhood maltreatment in 444 cases with schizophrenia and 292 healthy controls (from a total sample of 617 cases and 659 controls obtained from the Australian Schizophrenia Research Bank; ASRB). Participants subjected to any kind of maltreatment (including physical, emotional, or sexual abuse or physical or emotional neglect) in childhood were classified as 'exposed'; cognitive functioning was measured with Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test, and IQ was estimated with the Weschler Test of Adult Reading. Hierarchical regressions were used to test the main effects of genotype and childhood maltreatment, and their additive interactive effects, on cognitive function. For rs1360870, there were significant main effects of genotype and childhood maltreatment, and a significant interaction of genotype with childhood trauma affecting attention in both schizophrenia and healthy participants (C-homozygotes in both groups showed worse attention in the context of maltreatment); in SZ, this SNP also affected global neuropsychological function regardless of exposure to childhood trauma, with T-homozygotes showing worse cognition than other genotypes. The mechanisms of trauma-dependent effects of FKBP5 following early life trauma deserve further exploration in healthy and psychotic samples, in the context of epigenetic effects and perhaps epistasis with other genes. Study of these processes may be particularly informative in subgroups exposed to various other forms of early life adversity (i.e., birth complications, immigration).
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    • "Although contradictory findings have also been published (Bevilacqua et al., 2012), together, these results suggest that trauma and impulsivity may indeed exert a multiplier effect on interindividual cognitive emotion regulation differences. Previous studies established a clear link between impulsivity and emotional reactions after trauma exposure in clinical (abuse survivors: Brodsky et al., 2001; accident survivors: Joseph, Dalgleish, Thrasher, & Yule, 1997) and non-clinical samples alike (students: Aidman & Kollaras- Mitsinikos, 2006). "
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    ABSTRACT: Background: Traumatic exposure may modulate the expression of impulsive behavioral dispositions and change the implementation of emotion regulation strategies associated with depressive mood. Past studies resulted in only limited comprehension of these relationships, especially because they failed to consider impulsivity as a multifactorial construct. Objective: Based on Whiteside and Lynam’s multidimensional model that identifies four distinct dispositionalfacets of impulsive-like behaviors, namely urgency, (lack of) premeditation, (lack of) perseverance, and sensation seeking (UPPS), the current study used a sample of community volunteers to investigate whether an interaction exists between impulsivity facets and lifetime trauma exposure in predicting cognitive emotion regulation and depressive mood. Methods: Ninety-three adults completed questionnaires measuring lifetime trauma exposure, impulsivity, cognitive emotion regulation, and depressive mood. Results: Results showed that trauma-exposed participants with a strong disposition toward urgency (predisposition to act rashly in intense emotional contexts) tended to use fewer appropriate cognitive emotion regulation strategies than other individuals. Unexpectedly, participants lacking in perseverance (predisposition to have difficulties concentrating on demanding tasks) used more appropriate emotion regulation strategies if they had experienced traumatic events during their life than if they had not. Emotion regulation mediated the path between these two impulsivity facets and depressive mood. Conclusions: Together, these findings suggest that impulsivity has a differential impact on emotion regulation and depressive mood depending on lifetime exposure to environmental factors, especially traumatic events.
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    • "Emerging evidence has also begun to suggest that the brain-derived neurotrophic factor gene (BDNF) may be a plasticity gene (e.g., Chen, Li, & McGue, 2012; Gunnar et al., 2012; Juhasz et al., 2011; Mata, Thompson, & Gotlib, 2010; Suzuki et al., 2011), as is the oxytocin receptor gene (OXTR; Johansson et al., 2012; Poulin, Holman, & Buffone, 2012; Sturge-Apple, Cicchetti, Davies, & Suor, 2012) and the FK506 binding protein 5 gene (Bevilacqua et al., 2012; Xie et al., 2010; Zimmermann et al., 2011). There are perhaps less frequent indications of this in the catechol-O-methyltransferase gene (Laucht et al., 2012; Nijmeijer et al., 2010) and, in the previously reviewed literature, the monoamine oxidase A gene (MAOA; Enoch, Steer, Newman, Gibson, & Goldman, 2010; Wakschlag et al., 2010). "
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    ABSTRACT: We provide a theoretical and empirical basis for the claim that individual differences exist in developmental plasticity and that phenotypic plasticity should be a subject of study in its own right. To advance this argument, we begin by highlighting challenges that evolutionary thinking poses for a science of development and psychopathology, including for the diathesis-stress framework that has (fruitfully) guided so much empirical inquiry on developmental risk, resilience, and dysregulation. With this foundation laid, we raise a series of issues that the differential-susceptibility hypothesis calls attention to, while highlighting findings that have emerged over just the past several years and are pertinent to some of the questions posed. Even though it is clear that this new perspective on Person × Environment interaction is stimulating research and influencing how hypotheses are framed and data interpreted, a great many topics remain that need empirical attention. Our intention is to encourage students of development and psychopathology to treat phenotypic plasticity as an individual-difference construct while exploring unknowns in the differential-susceptibility equation.
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