Schizophrenia polygenic risk during typical development reflects multiscale cortical organization

Kirschner, M.; Paquola, C.; Khundrakpam, B.; Vainik, U.; Bhutani, N.; Hodzic-Santor, B.; Al-Sharif, N. B.; Misic, B.; Bernhardt, B.; Evans, A. C.; Dagher, A.

doi:10.1101/2021.06.13.448243

bioRxiv · 10.1101/2021.06.13.448243

Schizophrenia polygenic risk during typical development reflects multiscale cortical organization

Kirschner, M.·Paquola, C.·Khundrakpam, B.·Vainik, U.·Bhutani, N.·Hodzic-Santor, B.·Al-Sharif, N. B.·Misic, B.·Bernhardt, B.·Evans, A. C.·Dagher, A.

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Abstract

Schizophrenia is widely recognized as a neurodevelopmental disorder. Abnormal cortical development may by revealed using polygenic risk scoring for schizophrenia (PRS-SCZ). We assessed PRS-SCZ and cortical morphometry in typically developing children (3-21 years) using whole genome genotyping and T1-weighted MRI (n=390) from the Pediatric Imaging, Neurocognition and Genetics (PING) cohort. We contextualise the findings using (i) age-matched transcriptomics, (ii) histologically-defined cytoarchitectural types and functionally-defined networks, (iii) case-control differences of schizophrenia and other major psychiatric disorders. 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 vertex-wise cortical thickness were especially focused in the ventral attention network, while koniocortical type cortex (i.e. primary sensory areas) was relatively conserved from PRS-SCZ related differences. 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. Age group models illustrate a possible trajectory from PRS-SCZ associated cortical thickness increases in early childhood towards thinning in late adolescence, which resembles the adult brain phenotype of schizophrenia. Collectively, combining imaging-genetics with multi-scale mapping, our work provides novel insight into how genetic risk for schizophrenia impacts the cortex early in life.

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Kirschner, M., Paquola, C., Khundrakpam, B., Vainik, U., Bhutani, N., Hodzic-Santor, B., Al-Sharif, N. B., Misic, B., Bernhardt, B., Evans, A. C., Dagher, A.. 2021-06-13. Schizophrenia polygenic risk during typical development reflects multiscale cortical organization. https://doi.org/10.1101/2021.06.13.448243

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