Background: A fundamental question in biological psychiatry concerns the mechanisms that mediate between genetic liability and psychiatric symptoms. Genetic liability for Major Depressive Disorder (MDD) and Attention Deficit Hyperactivity Disorder (ADHD) often confer transdiagnostic risk to develop a wide variety of psychopathological symptoms through yet unknown pathways. Methods: We examined the psychological and cognitive pathways that might mediate the relationship between genetic liability (indexed by polygenic scores; PS) and broad psychopathology (indexed by the P-Factor and its underlying dimensions). We 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 dataset (4439 children, 2,081 females, 9-10 years old). Results: The association between MDD PS and psychopathology was partially mediated by punishment sensitivity and cognitive abilities: proportion mediated=13.96%. Particularly, this mediating role of punishment sensitivity was specific to the emotional/internalizing dimension of psychopathology while that of cognitive abilities was specific to externalizing and neurodevelopmental dimensions. Conversely, the influence of ADHD PS on psychopathology was partially mediated by reward sensitivity and cognitive abilities: proportion mediated=33.19%. This mediating role of reward sensitivity was focusing on the behavioral/externalizing and neurodevelopmental dimensions of psychopathology while that of cognitive abilities was more broadly across four dimensions. Conclusions: These findings provide a better understanding of how genetic risks for MDD and ADHD confer risk for psychopathology and suggest potential prevention/intervention targets for children at risk.

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