Monocytic Subsets and Their Signature Genes Differentially Impact Cortex and Cognition in First-Episode Schizophrenia

Accumulating evidence supports involvement of innate immunity in the pathophysiology of schizophrenia. Monocytes are a highly heterogeneous population, subcategorized into classical (CD14++CD16−), intermediate (CD14++CD16+) and nonclassical subsets (CD14+CD16++). How monocytic subsets may shape brain structures and functions remains unclear. The primary goal of this cross-sectional study was to investigate the inter-relationships among monocytic subsets and their specific transcriptomic profiles, cerebral cortical thickness, and cognitive functions in first-episode schizophrenia (FES) patients. We performed whole-blood RNA sequencing (RNAseq) in 128 FES patients and 111 healthy controls (HCs) along with MATRICS Consensus Cognitive Battery (MCCB) measurement, as well as neuroimaging and flow cytometry among partial participants. RNAseq revealed significantly changed expressions of 54 monocytic signature genes in FES patients compared to HCs, especially for intermediate and nonclassical monocytic subsets, with the most outstanding alterations being downregulated S100 Calcium Binding Protein A ( S100A ) and upregulated Interferon Induced Transmembrane Protein ( IFITM ) family members, respectively. The percentage of nonclassical monocytes was decreased in FES patients. Cortical thicknesses and MCCB performance were expectantly reduced in FES patients too. Interestingly, negative inter-relationships of monocytic signature genes with both cortical thicknesses and cognition were found in HCs, which were weakened or even reversed in FES patients. Furthermore, the lateral occipital cortex fully mediated the negative effect of a classical monocytic gene Ribonuclease A Family Member 2 ( RNASE2 ) on visual learning in patient group. This study suggests that monocytic dysfunctions play an essential role in cognitive deficit of schizophrenia, and their subtypes should be considered in future research. One Sentence Summary Dysfunctions of monocytic subsets play an essential role in cortex and cognitive deficit of schizophrenia