Relationships Between Polygenic Scores for Psychopathology and Observed Psychopathology Are Mediated by Cognitive Control and Reward Sensitivity Pathways: Insights From the ABCD Study.

Background: Psychiatric disorders affect approximately 20% of adolescents in the United States and are both heritable and highly polygenic. Polygenic scores (PGSs) aggregate genetic risk across the genome and in doing so potentially capture multiple, distinct behavioral pathways. Among these, cognitive control and reward sensitivity are key constructs that have been found to be independently and jointly related to adolescent psychopathology. Methods: In this study, we used latent variables representing cognitive control and reward sensitivity (measured at baseline) as mediators between PGSs for internalizing, neurodevelopmental, and addiction-related psychopathology and observed psychopathology measured 2 years later in the ABCD (Adolescent Brain Cognitive Development) Study ( Results: Our findings show that most of the associations between PGSs and later psychopathology were accounted for by indirect effects through cognitive control and reward sensitivity; all of the associations between the addiction PGS and externalizing were accounted for by the indirect effects, but less of the internalizing PGS to internalizing pathway was accounted for by control and reward sensitivity. Multiple cognitive control factors significantly mediated the effects of PGSs on both internalizing and externalizing outcomes (indirect effects = 0.004-0.074). Reward sensitivity, specifically sensation seeking, uniquely mediated the association between the addiction PGS and later psychopathology, suggesting that addiction-related genetic risk may operate through pathways related to heightened reward responsiveness. Conclusions: Overall, these results indicate that PGSs for internalizing, neurodevelopmental, and addiction-related traits index multiple distinct behavioral mechanisms with specific relevance to adolescent psychopathology risk.