Abstract
Schizophrenia is considered a polygenic disorder. People with schizophrenia and those with genetic high risk of schizophrenia (GHR) have presented with similar neurodevelopmental deficits in hemispheric asymmetry. The potential associations between neurodevelopmental abnormalities and schizophrenia-related risk genes in both schizophrenia and those with GHR remains unclear. To investigate the shared and specific alternations to the structural network in people with schizophrenia and those with GHR. And to identify an association between vulnerable structural network alternation and schizophrenia-related risk genes. A total of 97 participants with schizophrenia, 79 participants with GHR and 192 healthy controls, underwent diffusion tensor imaging (DTI) scans at a single site. We used graph theory to characterise hemispheric and whole-brain structural network topological metrics. For 26 people in the schizophrenia group and 48 in the GHR group with DTI scans we also calculated their schizophrenia-related polygenic risk scores (SZ-PRSs). The correlations between alterations to the structural network and SZ-PRSs were calculated. Based on the identified genetic-neural association, bioinformatics enrichment was explored. There were significant hemispheric asymmetric deficits of nodal efficiency, global and local efficiency in the schizophrenia and GHR groups. Hemispheric asymmetric deficit of local efficiency was significantly positively correlated with SZ-PRSs in the schizophrenia and GHR groups. Bioinformatics enrichment analysis showed that these risk genes may be linked to signal transduction, neural development and neuron structure. The schizophrenia group showed a significant decrease in the whole-brain structural network. The shared asymmetric deficits in people with schizophrenia and those with GHR, and the association between anomalous asymmetry and SZ-PRSs suggested a vulnerability imaging marker regulated by schizophrenia-related risk genes. Our findings provide new insights into asymmetry regulated by risk genes and provides a better understanding of the genetic-neural pathological underpinnings of schizophrenia.
Highlights
The shared asymmetric deficits in people with schizophrenia and those with genetic high risk of schizophrenia (GHR), and the association between anomalous asymmetry and SZ-polygenic risk score (PRS) suggested a vulnerability imaging marker regulated by schizophrenia-related risk genes
Our findings provide new insights into asymmetry regulated by risk genes and provides a better understanding of the genetic–neural pathological underpinnings of schizophrenia
The effect of diagnosis on HRSD, Hamilton Rating Scale for Anxiety (HRSA) and Brief Psychiatric Rating Scale (BPRS) scores was significant, with significantly higher HRSD, HRSA and BPRS scores in the schizophrenia group compared with the GHR and healthy control groups, and higher HRSD scores in the GHR group compared with the healthy control group
Summary
Schizophrenia is a highly heritable disorder with neurodevelopmental deficits – characterised by a failure to integrate neural processes as a result of an abnormal brain network.. Family studies reported a tenfold increased risk of developing schizophrenia in unaffected relatives of people with schizophrenia, and polygenic risk score (PRS) analysis was estimated to explain 7% of the variance in liability.. Family studies reported a tenfold increased risk of developing schizophrenia in unaffected relatives of people with schizophrenia, and polygenic risk score (PRS) analysis was estimated to explain 7% of the variance in liability.5 Identifying these potential imaging features could help explain the multilevel genetic–neural underpinnings of the development of schizophrenia. Post-mortem and neuroimaging studies in schizophrenia have repeatedly shown the condition to be associated with an anomalous pattern of hemispheric asymmetry. Crow and colleagues undertook a series of studies and proposed an influential theory: schizophrenia, which stems from the failure of normal hemispheric asymmetry in the temporal lobe region can be explained by genes. Crow et al indicated that hemispheric asymmetry in schizophrenia was unrelated to episode progression, and the anatomical asymmetry occurred during development. These neurodevelopmental alterations in hemispheric asymmetry were found both in brain structure and function, such as white matter architecture, cortical thickness and functional activation
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