Polygenic score for C-reactive protein is associated with accelerated cortical thinning and increased psychopathology in adolescents: a population-based longitudinal cohort study.

Adolescence is a critical neurodevelopmental window characterized by rapid cortical thinning, during which vulnerability to psychiatric disorders significantly increases. Although increased rates of cortical thinning have been associated with adverse mental health outcomes, the biological mechanisms underlying atypical neurodevelopment remain unclear. This study investigates whether genetic predisposition to systemic inflammation, assessed via polygenic scores for C-reactive protein (PGS_CRP), influences cortical thinning trajectories and psychopathology risk in adolescents. Using longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (baseline n=11,214; follow-up n=7,823), we found that higher genetic susceptibility to inflammation was associated with accelerated cortical thinning, particularly in medial temporal and insular regions (β = −0.013 ~ -0.018, p.FDR < 0.05), and increased externalizing psychopathology symptoms (β = 0.167, p.FDR < 0.05). Early-life infections independently predicted greater depressive and externalizing symptoms (β = 0.511 ~ 0.608, p.FDR < 0.05) but did not interact significantly with genetic predisposition. Structural equation modeling revealed that cortical thinning partially mediated the relationship between genetic inflammation risk and externalizing symptoms. Moreover, neurobiological annotation showed regional overlaps between inflammation-linked cortical thinning and neurotransmitter receptor gradients involving serotonin, GABA, cannabinoid, and glutamate systems. These findings provide evidence for genetic predisposition to inflammation as a factor in adolescent cortical maturation and behavioral outcomes, highlighting potential neuroimmune mechanisms underpinning vulnerability to mental health disorders during this sensitive developmental period.