Abstract
The A-kinase-anchoring protein 5 (AKAP5), a post-synaptic multi-adaptor molecule that binds G-protein-coupled receptors and intracellular signaling molecules has been implicated in emotional processing in rodents, but its role in human emotion and behavior is up to now still not quite clear. Here, we report an association of individual differences in aggressive behavior and anger expression with a functional genetic polymorphism (Pro100Leu) in the human AKAP5 gene. Among a cohort of 527 young, healthy individuals, carriers of the less common Leu allele (15.6% allele frequency) scored significantly lower in the physical aggression domain of the Buss and Perry Aggression Questionnaire and higher in the anger control dimension of the state-trait anger expression inventory. In a functional magnetic resonance imaging experiment we could further demonstrate that AKAP5 Pro100Leu modulates the interaction of negative emotional processing and executive functions. In order to investigate implicit processes of anger control, we used the well-known flanker task to evoke processes of action monitoring and error processing and added task-irrelevant neutral or angry faces in the background of the flanker stimuli. In line with our predictions, Leu carriers showed increased activation of the anterior cingulate cortex (ACC) during emotional interference, which in turn predicted shorter reaction times and might be related to stronger control of emotional interference. Conversely, Pro homozygotes exhibited increased orbitofrontal cortex (OFC) activation during emotional interference, with no behavioral advantage. Immunohistochemistry revealed AKAP5 expression in post mortem human ACC and OFC. Our results suggest that AKAP5 Pro100Leu contributes to individual differences in human aggression and anger control. Further research is warranted to explore the detailed role of AKAP5 and its gene product in human emotion processing.
Highlights
Statistical analysis To examine the overall influence of A-kinase-anchoring protein 5 (AKAP5) on measures of aggressive behavior and anger expression, we investigated the relationship between AKAP5 genotype and the four domains of the Buss–Perry aggression questionnaire (BPAQ) as well as four out of five domains of the STAXI as dependent variables
EFFECTS OF AKAP5 PRO100LEU ON HUMAN AGGRESSION AND ANGER To assess a potential influence of AKAP5 Pro100Leu on human aggression and anger, we systematically investigated genotypedependent group differences in well-established self-report questionnaires of aggressive behavior and anger expression in a cohort recruited from the interdisciplinary campus community of the University of Magdeburg, Germany
By using a multimodal approach including behavioral genetics, functional magnetic resonance imaging (fMRI) and post mortem immunohistochemistry, we could demonstrate that AKAP5 Pro100Leu is associated with human aggression and anger, with the Leu allele conferring a less aggressive phenotype with higher anger control
Summary
Functional neuroimaging studies have demonstrated that genetic variants linked to aggression and anger are associated with altered neuronal activation patterns during emotional processing (Meyer-Lindenberg et al, 2006; Buckholtz and Meyer-Lindenberg, 2008). Genetic studies on anger and aggression have focused on variants directly related to these transmitter systems, like receptors or metabolizing. The question arises whether genetic heterogeneity in these signaling cascades might influence interindividual variability in human anger and aggression. Initial evidence from depressed patients suggests that the transcription factor CREB, which is activated by GPCR signaling, shows genetic variations that affect human anger expression (Perlis et al, 2007), but the influence of genetic variations in intracellular signaling molecules on anger and aggression in the healthy population remains far unclear
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