A novel, biologically-informed polygenic score reveals role of mesocorticolimbic insulin receptor gene network on impulsivity and addiction

Importance Activation of brain insulin receptors occurs on mesocorticolimbic regions, modulating reward sensitivity and inhibitory control. Variations in the functioning of this mechanism likely associate with individual differences in the risk for related psychopathologies (attention-deficit hyperactivity disorder, addiction), an idea that agrees with the high comorbidity between insulin resistant states and psychiatric conditions. While genetic studies comprise an interesting tool to explore neurobiological mechanisms in community samples, the conventional genome-wide association studies and polygenic risk score methodologies completely ignore the fact that genes operate in networks, and code for precise biological functions in specific tissues. Objective We propose a novel, biologically informed genetic score reflecting the mesocorticolimbic insulin receptor-related gene network, and investigate if it predicts dopamine-related psychopathology (impulsivity and addiction) in community samples. Design Birth cohort (Maternal Adversity, Vulnerability and Neurodevelopment, MAVAN) and adult cohort (Study of Addiction, Genes and Environment, SAGE). Setting General community. Participants 212 4-year-old children (MAVAN), and 1626 adults (SAGE). Exposure The biologically informed, mesocorticolimbic specific, insulin receptor polygenic score was created based on levels of co-expression with the insulin receptor in striatum and prefrontal cortex, and calculated in the two samples using the genotype data (Psychip/Psycharray). Main outcome childhood impulsivity in the Information Sampling task, and risk for early addiction onset. Results The insulin receptor polygenic score showed improved prediction of childhood impulsivity in boys and risk for early addiction onset in males in comparison to conventional polygenic risk scores for attention-deficit hyperactivity disorder or addiction. Conclusions and relevance This novel genomic approach reveals insulin action as a relevant biological process involved in the risk for dopamine-related psychopathology. Key points Question Considering the modulation of mesocorticolimbic dopaminergic pathways by insulin through the action on its receptors (IR), we investigated if a novel, region specific polygenic score on the IR-related gene network (ePRS-IR) is associated with dopamine-related behaviors (impulsivity and addiction). Findings The ePRS-IR showed improved prediction of childhood impulsivity and risk for early addiction onset in comparison to conventional polygenic risk scores for ADHD or addiction. Meaning This novel genomic approach reveals insulin action as a biological process involved in the risk for dopamine-related psychopathology.