Motivation and Cognitive Abilities as Mediators between Polygenic Scores and Psychopathology in Children

Objective Fundamental questions in biological psychiatry concern the mechanisms that mediate between genetic liability and psychiatric symptoms. Genetic liability for many common psychiatric disorders often confers transdiagnostic risk to develop a wide variety of psychopathological symptoms through yet unknown pathways. We examine the psychological and cognitive pathways that might mediate the relationship between genetic liability (indexed by polygenic scores; PS) and broad psychopathology (indexed by p factor and its underlying dimensions). Method We first identified which of the common psychiatric PSs (major depressive disorder [MDD], attention-deficit/hyperactivity disorder [ADHD], anxiety, bipolar, schizophrenia, autism) were associated with p factor. We then focused on three pathways: punishment sensitivity (reflected by behavioral inhibition system; BIS), reward sensitivity (reflected by behavioral activation system; BAS) and cognitive abilities (reflected by g factor based on 10 neurocognitive tasks). We applied structural equation modeling on the Adolescent Brain Cognitive Development (ABCD) dataset (n=4,814; 2,263 female children; 9-10 years old). Results MDD and ADHD PSs were associated with p factor. The association between MDD PS and psychopathology was partially mediated by punishment sensitivity and cognitive abilities: proportion mediated= 22.35%. Conversely, the influence of ADHD PS on psychopathology was partially mediated by reward sensitivity and cognitive abilities: proportion mediated=30.04%. The mediating role of punishment sensitivity was specific to the emotional/internalizing. This mediating role of both reward sensitivity and cognitive abilities was focusing on the behavioral/externalizing and neurodevelopmental dimensions of psychopathology. Conclusion We provide a better understanding of how genetic risks for MDD and ADHD confer risks for psychopathology and suggest potential prevention/intervention targets for children at-risk.