Genetic Susceptibility to Schizophrenia and the Onset of Brain Developmental Change During Adolescence

Early neurodevelopmental manifestations of genetic vulnerabilities to psychopathology are crucial for understanding disease onset and informing early intervention. However, when genetic risks begin to manifest in the brain remains unclear.

We leveraged 2 large neurodevelopmental cohorts: the Adolescent Brain Cognitive Development (ABCD) Study in the United States and the Generation R (GenR) Study in the Netherlands. Repeated-measures brain imaging data were collected from 6228 individuals of European descent (mean baseline age 10 years), with an average follow-up of 2 (ABCD) to 4 (GenR) years. Using whole-brain vertexwise linear mixed models, we investigated how polygenic scores (PGSs) for 4 psychiatric disorders (attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder, schizophrenia [SCZ], major depressive disorder) and educational attainment were associated with brain morphological trajectories.

Children with low genetic susceptibility to SCZ showed expected increases in cortical surface area of the caudal middle and superior frontal regions during early adolescence, whereas those with higher genetic susceptibility showed decreases in these regions, suggesting divergent neurodevelopmental trajectories that may begin during this period. No significant associations were found between other psychiatric PGSs and brain structural changes over time. However, higher PGSs for educational attainment were associated with persistently larger surface areas, while higher PGSs for ADHD were related to persistently smaller surface areas in frontal and temporal lobes across time.

We showed that the impact of genetic susceptibility to SCZ may begin to manifest in the brain during early adolescence, revealing dynamic neurodevelopmental changes that may serve as potential biomarkers for early detection of SCZ.