Schizophrenia polygenic risk during typical development reflects multiscale cortical organization

Schizophrenia is widely recognized as a neurodevelopmental disorder, but determining neurodevelopmental features of schizophrenia requires a departure from classic case-control designs. Polygenic risk scoring for schizophrenia (PRS-SCZ) enables investigation of the influence of genetic risk for schizophrenia on cortical anatomy during neurodevelopment and prior to disease onset. PRS-SCZ and cortical morphometry were assessed in typically developing children (3 - 21 years) using T1-weighted MRI and whole genome genotyping (n=390) from the Pediatric Imaging, Neurocognition and Genetics (PING) cohort. Then, we sought to contextualise the findings using (i) age-matched transcriptomics, (ii) gradients of cortical differentiation and (iii) case-control differences of major psychiatric disorders. Higher PRS-SCZ was associated with greater cortical thickness in typically developing children, while surface area and cortical volume showed only subtle associations. Greater cortical thickness was most prominent in areas with heightened gene expression for dendrites and synapses. The pattern of PRS-SCZ associations with cortical thickness reflected functional specialisation in the cortex and was spatially related to cortical abnormalities of patient populations of schizophrenia, bipolar disorder, and major depression. Finally, age interaction models indicated PRS-SCZ effects on cortical thickness were most pronounced between ages 3 and 6, suggesting an influence of PRS-SCZ on cortical maturation early in life. Integrating imaging-genetics with multi-scale mapping of cortical organization, our work contributes to an emerging understanding of how risk for schizophrenia and related disorders manifest in early life.