Functional Connectome Hierarchy in Schizotypy and Its associations with Expression of Schizophrenia-Related Genes

Abstract Schizotype has been conceptualized as a continuum with symptoms of schizophrenia with marked genetic, neurobiological, sensory-cognitive overlaps. Hierarchical organization represents a general organizing principle for both the brain connectome supporting sensation-to-cognition continuum and gene expression patterns. However, the underlying changes in neuroimaging maps reflecting the cortical hierarchy that mechanistically link gene expressions to schizotypy are unclear. Using a large cohort of resting state-fMRI data from 1013 healthy young adults, the present study investigated schizotypy-associated sensorimotor-to-transmodal connectome hierarchy and assessed the connectome hierarchy similarity between schizotypy and schizophrenia. Furthermore, the normative and differential postmortem gene expression data were employed to investigate the transcriptional profiles associated with the schizotypy-associated connectome hierarchy. We found that schizotypy was associated with a compressed functional connectome hierarchy, including compressed global topography and focal alterations in sensory and transmodal cognitive areas, suggesting diminished functional system differentiation. Interestingly, the pattern of schizotypy-related hierarchy is tightly correlated with the pattern of hierarchy organization observed in schizophrenia. Notably, schizotypy-related connectome hierarchy was most closely colocated with expression of schizophrenia-related genes compared with other psychiatric disorders, with the correlated genes being enriched in biological processes well-known involved in schizophrenia, i.e., transsynaptic and receptor signaling, calcium ion binding, and channel activity. These findings not only shed light on the neurobiological and molecular genetic mechanisms underlying the sensory-cognitive deficits in schizotypy, but also provide new insights into the neurobiological continuum of psychosis thus advanced our understanding of how genetic propensity for schizophrenia-alike traits play an enduring role in creating biological vulnerability to psychosis.