Relative to neurons, we identified more than twice as many DEGs in glial cells between unaffected individuals and individuals with OUD (Figs. 2b, 4a). The number of DEGs were independent of cell type proportions and sequencing depth, as microglia and endothelial cells had the most DEGs among glial cells, and expression patterns were largely distinct between glial cell types (Fig. S6). An exception was the robust enrichment of genes involved in interferon response in multiple glial cell types, including astrocytes and oligodendrocytes (Fig. 5c). Interferon response genes were significantly upregulated in all glial cell types in individuals with OUD (FDR < 0.047, Supplementary Data 1–S11), with the following interferon-related hub genes: CMP2, HLA-F, IFI44, PPM1B, and RSAD2 (Fig. 5a). We also observed an upregulation of the NFKB1 transcription factor gene regulatory module in astrocytes (Fig. 5b, e), and the upregulation of the STAT3 module in oligodendrocyte precursor cells (OPC,FDR < 0.036; Fig. 5b). Several of the predicted NFKB1 gene targets were also differentially expressed including the inhibitor of this pathway, NFKBIA (log2FC = 1.86, FDR = 0.039; Fig. 5e). Other
