The identification of differentially expressed transcription factor gene regulatory modules across glial cell types highlights several key factors in the regulation of immune response related to OUD. In oligodendrocyte precursor cells, the CEBPB module was upregulated in OUD (FDR = 0.031; Fig. 5b, e), with prior studies showing diverse functions of CEBPB in proinflammatory states92 and the direct regulation of APOE in Alzheimer’s disease-related pathologies93,94. Notably, APOE is concordantly upregulated in oligodendrocyte precursor cells (log2FC = 2.56, FDR = 5.9e-4), along with other predicted CEBPB targets (Fig. 5b, e). The RXRG transcription factor-gene regulatory module, which was downregulated in neuronal subtypes, was also downregulated in microglia (Fig. 5b, e, FDR = 0.027). An inferred target of RXRG is FOXP2 (Fig. 5e), which was recently associated with OUD and other substance use disorders at the genome-wide level95. FOXP2 expression in microglia may be unique to humans compared to other primates. Thus, downregulation of the FOXP2 transcription factor gene regulatory module in human microglia may link the genetic risk of OUD to other addiction risk traits96,97.
