Association of astrocyte-specific gene expression in the dorsolateral prefrontal cortex with clozapine treatment in schizophrenia.

Gene expression profiling studies could be a valuable tool in identifying the specific genes and pathways involved in the mechanism of action of clozapine, leading to a better understanding of the molecular biology underlying treatment-resistant schizophrenia (TRS). We aimed to identify the co-expressed modules that reflect the genetic differences between clozapine-treated and non-clozapine-treated patients with schizophrenia as a proxy of TRS. Gene expression of DLPFC samples from 26 subjects with schizophrenia (13 clozapine treated and 13 non-clozapine treated) were analyzed using Clariom S Human Array. Weighted gene coexpression network analysis (WGCNA) was applied to identify modules of co-expressed genes and to test its association with clozapine treatment. As a result of our analysis of the gene co-expression architecture in the DLPFC, among the 13 modules identified, one module (green) was significantly associated with clozapine treatment (p = 3.7 × 10−2). This module was significantly enriched in astrocyte markers (5.7 × 10−29) and genes involved in the polygenic architecture of TRS (1.6 × 10−2). This finding provides cell type-specific associations that could help in the interpretation of the neurobiological basis of TRS. A better understanding of the specific DLPFC cell types involved in clozapine treatment will contribute to the study of potential pathways and ultimately help improve psychiatric classification tools in personalized medicine.