Coexpression of the discoidin domain receptor 1 gene with oligodendrocyte-related and schizophrenia risk genes in the developing and adult human brain.

ABSTRACT

BACKGROUND: Discoidin domain receptor tyrosine kinase 1 (DDR1) is present in multiple types of epithelial cells and is highly expressed in the nervous system. Previous studies have revealed that DDR1 is involved in schizophrenia (SCZ). Although the expression of DDR1 in oligodendrocytes has been described, its role in brain myelination is not well understood. In this study, we aimed to explore the coexpression network of DDR1 in the human brain and to compare the list of DDR1 coexpressing genes with the list of genes containing single nucleotide polymorphisms (SNPs) that are associated with SCZ. MATERIALS AND METHODS: We used a weighted gene coexpression network analysis (WGCNA) of a dataset from four brain areas (the dorsolateral prefrontal cortex, primary motor cortex, hippocampus, and striatum) and from four different intervals (I) of life (I-1 = 10-38 weeks postconception, I-2 ≥0 to < 6 years, I-3 ≥ 6 to < 40 years, and I-4 ≥ 40 years of age). We compared the list of genes that are associated with SCZ in the GWAS Catalog with the list of genes coexpressing with DDR1 in each interval. RESULTS: Our study revealed that DDR1 was coexpressed with oligodendrocyte-related genes mainly in I-2 (adjP = 5.66e-24) and I-3 (adjP = 2.8e-114), which coincided with the coexpression of DDR1 with myelination-related genes (adjP = 9.04e-03 and 2.51e-08, respectively). DDR1 was also coexpressed with astrocyte-related genes in I-1 (adjP = 1.11e-71), I-2 (adjP = 2.12e-20) and I-4 (adjP = 9.93e-52) and with type 2 microglia-related genes in I-1 (adjP = 2.84e-08), I-2 (adjP = 5.68e-16) and I-4 (adjP = 3.66e-10). Moreover, we observed significant enrichment of SCZ susceptibility genes within the coexpression modules containing DDR1 in I-1 and I-4 (P = 1e-04 and 0.0037, respectively), during which the DDR1 module showed the highest association with the astrocytes. CONCLUSIONS: Our study confirmed that DDR1 is coexpressed with oligodendrocyte- and myelin-related genes in the human brain but suggests that DDR1 may contribute mainly to SCZ risk through its role in other glial cell types, such as astrocytes.