Abstract
The etiology of schizophrenia is multi-factorial with early neurodevelopmental antecedents, likely to result from a complex interaction of genetic and environmental risk. However, few studies have examined how schizophrenia polygenic risk scores (PRS) are moderated by environmental factors in shaping neurodevelopmental brain structure, prior to the onset of psychotic symptoms. Here, we examined whether hair cortisol, a quantitative metric of chronic stress, moderated the association between genetic risk for schizophrenia and pre-adolescent brain structure.This study was embedded within the Generation R Study, involving pre-adolescents of European ancestry assessed regarding schizophrenia PRS, hair cortisol, and brain imaging (n = 498 structural; n = 526 diffusion tensor imaging). Linear regression was performed to determine the association between schizophrenia PRS, hair cortisol level, and brain imaging outcomes.Although no single measure exceeded the multiple testing threshold, nominally significant interactions were observed for total ventricle volume (Pinteraction = 0.02) and global white matter microstructure (Pinteraction = 0.01) – two of the most well replicated brain structural findings in schizophrenia.These findings provide suggestive evidence for the joint effects of schizophrenia liability and cortisol levels on brain correlates in the pediatric general population. Given the widely replicated finding of ventricular enlargement and lower white matter integrity among schizophrenia patients, our findings generate novel hypotheses for future research on gene-environment interactions affecting the neurodevelopmental pathophysiology of schizophrenia.
Highlights
Schizophrenia is a highly heritable psychiatric disorder, mediated through a complex combination of common and rare genetic variants (Sullivan et al, 2003)
Studies that assess how genetic risk for schizophrenia is related to variations in structural brain correlates are important, given that both gray matter and white matter microstructural correlates have been consistently observed in patients with schizophrenia (Brugger and Howes, 2017; Kelly et al, 2018; van Erp et al, 2016, 2018), and this has been replicated in childhood-onset schizophrenia samples (Tamnes and Agartz, 2016) and first-episode psychosis patients (FusarPoli et al, 2014)
Schizophrenia Polygenic risk scores (PRS) was associated with lower ventricular volume (Pt < 0.0005: β=-0.13, 95% CI -0.21;-0.04, P = 0.01), but this not survive false discovery rate (FDR)-correction for multiple testing (PFDR-adjusted = 0.30)
Summary
Schizophrenia is a highly heritable psychiatric disorder, mediated through a complex combination of common and rare genetic variants (Sullivan et al, 2003). Studies that assess how genetic risk for schizophrenia is related to variations in structural brain correlates are important, given that both gray matter and white matter microstructural correlates have been consistently observed in patients with schizophrenia (Brugger and Howes, 2017; Kelly et al, 2018; van Erp et al, 2016, 2018), and this has been replicated in childhood-onset schizophrenia samples (Tamnes and Agartz, 2016) and first-episode psychosis patients (FusarPoli et al, 2014). No prior studies have assessed the interaction between genetic and stress-related environmental risk factors on childhood brain development, despite that schizophrenia pathophysiology is widely hypothesized to have early neurodevelopmental antecedents that are sensitive to the environmental stressors (van Os et al, 2010)
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