Prefrontal Granule Cell-Related Genes and Schizophrenia

Abstract Although both the granular layer of the prefrontal cortex (PFC) and schizophrenia are unique in primates, especially humans, their linkage is unclear. Here, we tested whether schizophrenia is associated with expression profiles of the granule cell (GC)-related genes in the human PFC. We identified 14 candidate GC-related genes with gradually increased expression levels along the gradient of the agranular, dysgranular, light-granular, and granular prefrontal regions based on the densely sampled gene expression data of 6 postmortem human brains, and with more than 10-fold expression in neurons than other cell types based on the single-cell RNA-sequencing data of the human PFC. These GC-related genes were functionally associated with synaptic transmission and cell development and differentiation. The identified 14 GC-related genes were significantly enriched for schizophrenia, but not for depression and bipolar disorder. The expression levels of the 4 stable schizophrenia- and GC-related genes were spatially correlated with gray matter volume differences in the PFC between patients with schizophrenia and healthy controls. This study provides a set of candidate genes for the human prefrontal GCs and links expression profiles of the GC-related genes to the prefrontal structural impairments in schizophrenia.