Background: Schizophrenia (SCZ) and genetic high-risk (GHR) individuals exhibit deficits in brain functional networks and cognitive function, potentially impacted by SCZ risk genes. This study aims to delineate these impairments in SCZ and GHR individuals, and further explore how risk genes affect brain networks and executive function.
Methods: A total sample size of 292 participants (100 SCZ, 68 GHR, and 124 healthy controls [HCs]) in the study. The Wisconsin Card Sorting Test (WCST) and resting-state functional magnetic resonance imaging (rs-fMRI) are utilized to evaluate executive function and brain network topology. SCZ-related polygenic risk scores (SCZ-PRS) were used to evaluate genetic risk levels. WCST and PRS were not applied to all participants.
Results: Significant reductions in nodal efficiency and degree centrality (Dnodal) were observed within the right median cingulate and paracingulate gyri (MCPG_R) in both SCZ and GHR groups, compared to HCs. There were significant correlations between SCZ-PRS, Dnodal in MCPG_R, and WCST scores. Moreover, Dnodal in MCPG_R completely mediated the relationship between SCZ-PRS and executive function. The enrichment analysis of these risk genes indicates their involvement in biological processes of signal transduction and synaptic transmission.
Conclusions: This study highlights the pivotal role of impaired cingulate function in mediating the effects of genetic risks on executive deficits, offering new insights into the genetic-neuro-cognitive nexus in schizophrenia and potential targets for clinical interventions.
Keywords: brain networks; cognitive function; functional neuroimaging; polygenic risk scores; schizophrenia.