The identification of heritable mechanisms that link genes to complex clinical phenotypes is a critical step in mapping the developmental course of psychiatric disorders. We leveraged recent methodological advances in modeling the polygenic architecture of externalizing to uncover novel neural phenotypes for this spectrum of disorders. The externalizing PS predicted hyper-connectivity in a distributed brain network that included prefrontal (PFC) and subcortical regions critical for salience processing, emotion regulation, reinforcement learning, and impulse control. Directional analyses revealed that subcortical regions influenced PFC to a greater extent in participants with stronger polygenic associations with externalizing, whereas the opposite direction of influence was observed for those with weaker polygenic associations. The externalizing PS was associated with the organization of network nodes, specifically higher Participation Coefficient for bilateral amygdala and left rACC. Findings provide preliminary support that disturbed resting-state connectivity in this brain circuit is a genetically-influenced mechanism associated with the manifestation of disinhibited behaviors and alcohol/substance disorders.
