Linking Genetics to Behavior: From Glutamatergic Genetic Variation Via Amygdala Morphology and Fear Recognition to...

Although glutamatergic genetic variation, reduced amygdala volume, and impaired fear recognition have been linked to callous-unemotional (CU) traits and aggression, the pathways connecting these constructs remain unclear. Therefore, we examined associations between genetic proxies for glutamine/glutamate blood levels and CU traits; reactive and proactive aggression; and the mediating role of amygdala morphology and fear recognition.

Our pooled case-control sample consisted of 278 youths (8-18 years, n_male = 203) with (n = 177) and without (n = 101) clinically significant aggressive behavior and/or disruptive behavior disorders who participated in a European multicenter study. We used continuous scores for CU traits and aggression, polygenic scores (PGSs) for blood levels of glutamine/glutamate, and T1-weighted magnetic resonance images for calculating amygdala volume and vertexwise shape analyses. We applied path analysis to test direct and total associations and mediation effects.

Glutamine PGS was negatively associated with CU traits. Glutamate PGS was positively associated with amygdala volume and fear recognition, which in turn were negatively associated with CU traits and proactive aggression; fear recognition was also associated with reactive aggression. The total path between glutamate PGS and CU traits was also significant and was mediated by fear recognition.

Our results suggest that glutamatergic genetic variation 1) is associated with CU traits; 2) is associated with amygdala volume and fear recognition; and 3) is indirectly associated with CU traits through fear recognition. Overall, we provide support for an etiological pathway underlying CU traits encompassing glutaminergic/glutamatergic genetic variation, amygdala volume, and fear recognition and the relevance of using PGSs for glutamate/glutamine blood metabolites.