Coexpression network analysis of the adult brain sheds light on the pathogenic mechanism of DDR1 in schizophrenia and bipolar disorder

Abstract

DDR1 has been linked to schizophrenia (SCZ) and bipolar disorder (BD) in association studies. DDR1 encodes 58 distinct transcripts, which can be translated into five isoforms (DDR1a-e) and are expressed in the brain. However, the transcripts expressed in each brain cell type, their functions and their involvement in SCZ and BD remain unknown. Here, to infer the processes in which DDR1 transcripts are involved, we used transcriptomic data from the human brain dorsolateral prefrontal cortex of healthy controls (N = 936) and performed weighted gene coexpression network analysis followed by enrichment analyses. Then, to explore the involvement of DDR1 transcripts in SCZ (N = 563) and BD (N = 222), we studied the association of coexpression modules with disease and performed differential expression and transcript significance analyses. Some DDR1 transcripts were distributed across five coexpression modules identified in healthy controls (M_HC). M_HC1 and M_HC2 were enriched in the cell cycle and proliferation of astrocytes and OPCs; M_HC3 and M_HC4 were enriched in oligodendrocyte differentiation and myelination; and M_HC5 was enriched in neurons and synaptic transmission. Most of the DDR1 transcripts associated with SCZ and BD pertained to M_HC1 and M_HC2. Altogether, our results suggest that DDR1 expression might be altered in SCZ and BD via the proliferation of astrocytes and OPCs, suggesting that these processes are relevant in psychiatric disorders.