Abstract
Abstract Schizophrenia is a heritable neurodevelopmental disorder characterized by neuroanatomical changes in the brain, but exactly how increased genetic burden for schizophrenia influences brain structure is unknown. Similarly, how environmental risk factors for schizophrenia impact brain structure is not fully understood. Here we investigated how genetic burden for schizophrenia (indexed by a polygenic risk score, PRS-SCZ) was associated with cortical thickness (CT), surface area (SA), cortical volume (CV), and subcortical structures within 18 088 White British ancestry participants with derived brain phenotypes from UK Biobank. We also explored whether environmental risk factors for schizophrenia (childhood trauma, cannabis use, birth weight, season of birth, and Townsend social deprivation index) exacerbated the impact of PRS-SCZ on brain structure. We found that PRS-SCZ was associated with lower CT in the frontal lobe, insula lobe, lateral orbitofrontal cortex, medial orbitofrontal cortex, posterior cingulate cortex, and inferior frontal cortex, and reduced SA and CV in the supramarginal and superior temporal cortex, but not with subcortical volumes. When models included environmental risk factors as covariates, PRS-SCZ was only associated with lower SA/CV within the supramarginal cortex, superior temporal cortex, and inferior frontal cortex. Moreover, no interactions were observed between PRS-SCZ and each of the environmental risk factors on brain structure. Overall, we identified brain structural correlates of PRS-SCZ predominantly within frontal and temporal regions and some of these associations were independent of environmental risk factors, suggesting that they may represent vulnerable biomarkers of genetic risk for schizophrenia. Future research is warranted to establish these associations beyond older White British individuals.
Highlights
Schizophrenia is a debilitating and complex psychiatric disorder, affecting about 1% of the population.[1]
Participants were excluded for the following reasons: having a developmental or neurological disorder (See Supplementary Table S1 for detailed participant exclusion criteria); selfreported schizophrenia; having withdrawn from the UK Biobank project; non-White British ancestry based on self-report and genetic data; genetic data failing to pass quality control and having an intracranial volume or a polygenic risk scores for schizophrenia (PRS-SCZ) beyond three standard deviations from the sample mean
Considering the potential impact of environmental risk factors, we investigated whether associations between PRS-SCZ and brain measures were significant when childhood trauma, cannabis use, birth weight, season of birth, and Townsend deprivation index were included as additional covariates
Summary
Schizophrenia is a debilitating and complex psychiatric disorder, affecting about 1% of the population.[1] It is a heritable neurodevelopmental condition that arises via a complex interaction of genetic and environmental risk factors.[2] Neuroimaging studies have reported brain structural alterations in cortical and subcortical regions in people with schizophrenia relative to healthy individuals.[3,4,5,6] These brain changes could be driven by genetic factors and may mediate the effect of genetic risk on the phenotype of schizophrenia.[7,8,9] Genome-wide association studies (GWAS) have identified hundreds of significant loci and indicate a polygenic architecture of schizophrenia.[8,10,11] A polygenic risk score for schizophrenia, which captures the cumulative effect of significant risk loci across the whole genome, is useful in exploring the neurobiology of schizophrenia.[12,13,14] To date, little is known about how polygenic risk for schizophrenia influences brain structure, or how environmental risk factors may influence these associations
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