Schizophrenia polygenic risk during typical development reflects multiscale cortical organization

Abstract

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.

Associations between brain imaging and polygenic scores of mental health and educational attainment in children aged 9-11

“…Importantly, these psychiatric PRS were associated with a multimodal brain imaging pattern above and beyond the dimensional clinical symptoms modeled here. In addition to showing higher thickness globally, which is consistent with recent reports in youth samples (15), it revealed regional shape differences in the lateral and medial temporal cortex, and white matter tracts connecting the hippocampus, a region previously associated with schizophrenia (12,81,82). Many biological processes may underlie the observed signals as imaging modalities are sensitive but not specific to single biological processes.…”

“…Following past reports, we hypothesized that all imaging measures would show moderate to high heritability (L. T. Elliott et al, 2018; Grasby et al, 2020; Li et al, 2018; Schmitt et al, 2020; Strike et al, 2019) and expected small and widespread associations between PRS of psychiatric disorders and brain imaging components (Alnæs et al, 2019; Kirschner et al, 2021; Westlye et al, 2019). As a result, we here attempt to provide a more complete picture of the genetic effects on brain structure during this important developmental period.…”

“…Research in younger population samples is at present scarce and current small sample sizes may hinder the power to detect small effects. Nonetheless, recent studies point to cortical differences in individuals with high PRS already observed in youth (Khundrakpam et al, 2020; Kirschner et al, 2021).…”

“…Research in younger population samples is at present scarce and current small sample sizes may hinder the power to detect small effects. Nonetheless, recent studies point to cortical differences in individuals with high PRS already observed in youth (Khundrakpam et al, 2020;Kirschner et al, 2021). Psychiatric disorders are highly polygenic and are thus likely to have distributed effects on the brain (Birnbaum and Weinberger, 2017;Insel, 2010;Ripke et al, 2020), possibly observed in multiple neuroimaging modalities that are sensitive to different tissue properties (Lazari et al, 2021;Natu et al, 2019;Ripke et al, 2020;Rokicki et al, 2021).…”

Associated genetics and connectomic circuitry in schizophrenia and bipolar disorder

“…Schizophrenia and bipolar disorder share a common genetic background and molecular pathways (10,11,63). Our results extend these observations suggesting that normative variations of macroscale brain circuitry are associated with combined polygenic effects of schizophrenia and bipolar disorder, findings that are in support of a general relationship between polygenic liability and structural (64,65) and functional brain organization (23,66).…”