FKBP5 interacts with maltreatment in children with extreme, pervasive, and persistent aggression

Bryushkova, Lyubov; Zai, Clement C.; Sheng, Chen; Pappa, Irene; Mileva, Viara; Tiemeier, Henning; Bakermans‐Kranenburg, Marian J.; Kennedy, James L.; Beitchman, Joseph H.

doi:10.1016/j.psychres.2015.09.052

Cited by 12 publications

(9 citation statements)

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“…Both childhood trauma and callous unemotional traits are robustly associated with aggression and related conduct problems during adolescence and adulthood (Hare and Neumann, 2009 ; Frick and Ray, 2015 ; Milaniak and Widom, 2015 ; Gillikin et al, 2016 ). Moreover, there is growing empirical support that the FKBP5 gene plays a key role in the modulation of the stress response and the regulation of emotion, including risk for aggressive behavior (Klengel et al, 2013 ; Bryushkova et al, 2016 ), and the present study is the first to demonstrate this relationship in adults, and the first to demonstrate an association between aggression and the T allele of rs1360780. While beyond the scope of the present data, it is possible that the predictive utility of FKBP5 and CTQ abuse variables result from the presence of a gene × environment phenotype (Tuvblad and Baker, 2011 ).…”

Section: Discussionsupporting

confidence: 63%

“…Specifically, certain FKBP5 variants appear to modulate clinically relevant aspects of mood and behavior in the context of childhood trauma and post-traumatic stress disorder (Klengel et al, 2013 ; Klengel and Binder, 2015 ; Zannas et al, 2016 ), as well as other stress-related pathologies via interaction with the glucocorticoid receptor (Bevilacqua and Goldman, 2011 ; Zannas et al, 2016 ). For example, FKBP5 gene × environment interactions play a role in depression (Gillespie et al, 2009 ; Appel et al, 2011 ; Tozzi et al, 2016 ), and—relevant to the present report—aggressive behavior in children (Bevilacqua et al, 2012 ; White et al, 2012 ; Bryushkova et al, 2016 ). Importantly, genetic variation for FKBP5 has not been tested as a predictor of aggressive behavior in adults.…”

Section: Introductionmentioning

confidence: 68%

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Genetic and Psychosocial Predictors of Aggression: Variable Selection and Model Building With Component-Wise Gradient Boosting

Suchting

Gowin

Green

et al. 2018

Front. Behav. Neurosci.

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Rationale: Given datasets with a large or diverse set of predictors of aggression, machine learning (ML) provides efficient tools for identifying the most salient variables and building a parsimonious statistical model. ML techniques permit efficient exploration of data, have not been widely used in aggression research, and may have utility for those seeking prediction of aggressive behavior.Objectives: The present study examined predictors of aggression and constructed an optimized model using ML techniques. Predictors were derived from a dataset that included demographic, psychometric and genetic predictors, specifically FK506 binding protein 5 (FKBP5) polymorphisms, which have been shown to alter response to threatening stimuli, but have not been tested as predictors of aggressive behavior in adults.Methods: The data analysis approach utilized component-wise gradient boosting and model reduction via backward elimination to: (a) select variables from an initial set of 20 to build a model of trait aggression; and then (b) reduce that model to maximize parsimony and generalizability.Results: From a dataset of N = 47 participants, component-wise gradient boosting selected 8 of 20 possible predictors to model Buss-Perry Aggression Questionnaire (BPAQ) total score, with R2 = 0.66. This model was simplified using backward elimination, retaining six predictors: smoking status, psychopathy (interpersonal manipulation and callous affect), childhood trauma (physical abuse and neglect), and the FKBP5_13 gene (rs1360780). The six-factor model approximated the initial eight-factor model at 99.4% of R2.Conclusions: Using an inductive data science approach, the gradient boosting model identified predictors consistent with previous experimental work in aggression; specifically psychopathy and trauma exposure. Additionally, allelic variants in FKBP5 were identified for the first time, but the relatively small sample size limits generality of results and calls for replication. This approach provides utility for the prediction of aggression behavior, particularly in the context of large multivariate datasets.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 68%

Genetic and Psychosocial Predictors of Aggression: Variable Selection and Model Building With Component-Wise Gradient Boosting

Suchting

Gowin

Green

et al. 2018

Front. Behav. Neurosci.

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“…Following a disaster, perhaps youth with a specific genotype or neural dysfunction may be more likely to manifest trauma response through the development of co-occurring PTS and CPs. For example, research has shown that genetic variations interact with maltreatment to influence youth aggression (Bryushkova et al, 2016), and youth Respiratory Sinus Arrhythmia before a natural disaster predicts post-disaster PTSD symptoms (Mikolajewski & Scheeringa, 2018). Similar physiological and neural pathways are implicated in youth PTS and CPs (e.g., Blair, Veroude, & Buitelaar, 2018; Morey, Haswell, Hooper, & De Bellis, 2016), perhaps accounting in part for the overrepresentation of CP among youth with the most severe PTS.…”

Section: Discussionmentioning

confidence: 99%

A Latent Profile Analysis of Co-occurring Youth Posttraumatic Stress and Conduct Problems Following Community Trauma

et al. 2018

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Although most research with youth exposed to violent manmade disasters has focused on internalizing problems, recent work suggests conduct problems (CPs) may also manifest in exposed youth. However, the extent to which youth postevent CPs present independently, versus co-present in conjunction with PTSD symptoms, remains unclear. The present study examined PTS and CP symptom profiles among affected Boston-area youth following the 2013 Boston Marathon bombing. This study used latent profile analysis to identify distinct PTS and CP symptom profiles among Boston-area youth ages 4–19 years (N=344) affected by the Boston Marathon bombing events. PTS and CPs were measured using the UCLA-PTSD-RI and the SDQ parent reports, respectively. Analyses identified 3 distinct profiles: presentations characterized by (a) low PTS, low CPs, (b) moderate PTS, low CPs, and (c) high PTS, elevated CPs. The profile characterized by the highest PTS was the only profile with elevated CPs; hyperarousal and emotional numbing/avoidance symptoms showed the greatest distinguishing properties among profiles with and without elevated CP. Types of traumatic exposure experienced by youth were differentially associated with profiles. Specifically, direct (but not relational) exposure distinguished youth classified in the profile showing elevated CPs. Findings suggest interventions following violent manmade disasters may do well to incorporate CP modules when working with youth showing the greatest hyperarousal and emotional numbing, and/or who have directly witnessed the most violence.

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“…Finally, the FKBP5 gene, which codes a co-chaperone of the glucocorticoid receptor that regulates its sensitivity, has been extensively investigated for its role in mediating stress, hormonal, and immune responses to adverse experiences, particularly in the context of gene–environment interactions (Zannas & Binder, 2014). For example, FKBP5 polymorphisms have been found to interact with childhood trauma (e.g., maltreatment) to predict a range of psychiatric outcomes, including childhood aggression (Bryushkova et al, 2016). While emerging evidence suggests that FKBP5 methylation may mediate these observed Gene × Environment interactions (Zannas, Wiechmann, Gassen, & Binder, 2015), more work is needed to characterize its relevance to CP behavior.…”

Section: Discussionmentioning

confidence: 99%

Neonatal DNA methylation and early-onset conduct problems: A genome-wide, prospective study

et al. 2017

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2017). Neonatal DNA methylation and early-onset conduct problems: A genome-wide, prospective study. Development and Psychopathology, 1-15. DOI: 10.1017/S095457941700092XCiting this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policyIf you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access to the work immediately and investigate your claim. (0)207 848 0992 Development & Psychopathology.DNA methylation and conduct problems 2 AbstractEarly-onset conduct problems (CP) are a key predictor of adult criminality and poor mental health. While previous studies suggest that both genetic and environmental risks play an important role in the development of early-onset CP, little is known about potential biological processes underlying these associations. In this study, we examined prospective associations between DNA methylation (cord blood at birth) and trajectories of CP (4-13yrs), using data drawn from the Avon Longitudinal Study of Parents and Children (ALSPAC). Methylomic variation at seven loci across the genome (FDR<0.05) differentiated children who go on to develop early-onset (n = 174) vs low (n = 86) CP, including sites in the vicinity of MGLL (involved in endocannabinoid signaling and pain perception). Sub-threshold associations in the vicinity of three candidate genes for CP (MAOA, BDNF, and FKBP5) were also identified. Within the early-onset CP group, methylation levels of the identified sites did not distinguish children who will go on to persist vs desist in CP behavior over time. Overall, we found that several of the identified sites correlated with prenatal exposures, and none were linked to known genetic mQTLs. Findings contribute to a better understanding of epigenetic patterns associated with early-onset CP.

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FKBP5 interacts with maltreatment in children with extreme, pervasive, and persistent aggression

Cited by 12 publications

References 35 publications

Genetic and Psychosocial Predictors of Aggression: Variable Selection and Model Building With Component-Wise Gradient Boosting

Genetic and Psychosocial Predictors of Aggression: Variable Selection and Model Building With Component-Wise Gradient Boosting

A Latent Profile Analysis of Co-occurring Youth Posttraumatic Stress and Conduct Problems Following Community Trauma

Neonatal DNA methylation and early-onset conduct problems: A genome-wide, prospective study

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