Schizophrenia Polygenic Risk During Typical Development Reflects Multiscale Cortical Organization

Background: Schizophrenia is widely recognized as a neurodevelopmental disorder. Abnormal cortical development in otherwise typically developing children and adolescents may be revealed using polygenic risk scores for schizophrenia (PRS-SCZ).

Methods: We assessed PRS-SCZ and cortical morphometry in typically developing children and adolescents (3-21 years, 46.8% female) using whole-genome genotyping and T1-weighted magnetic resonance imaging (n = 390) from the PING (Pediatric Imaging, Neurocognition, and Genetics) cohort. We contextualized the findings using 1) age-matched transcriptomics, 2) histologically defined cytoarchitectural types and functionally defined networks, and 3) case-control differences of schizophrenia and other major psychiatric disorders derived from meta-analytic data of 6 ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) working groups, including a total of 12,876 patients and 15,670 control participants.

Results: Higher PRS-SCZ was associated with greater cortical thickness, which was most prominent in areas with heightened gene expression of dendrites and synapses. PRS-SCZ-related increases in vertexwise cortical thickness were mainly distributed in association cortical areas, particularly the ventral attention network, while relatively sparing koniocortical type cortex (i.e., primary sensory areas). The large-scale pattern of cortical thickness increases related to PRS-SCZ mirrored the pattern of cortical thinning in schizophrenia and mood-related psychiatric disorders derived from the ENIGMA consortium. Age group models illustrate a possible trajectory from PRS-SCZ-associated cortical thickness increases in early childhood toward thinning in late adolescence, with the latter resembling the adult brain phenotype of schizophrenia.

Conclusions: Collectively, combining imaging genetics with multiscale mapping, our work provides novel insight into how genetic risk for schizophrenia affects the cortex early in life.