SPI1 (Spi-1 Proto-Oncogene) encodes an ETS-domain transcription factor (PU.1) that regulates gene expression during myeloid and B-lymphoid cell development and homeostasis. This nuclear protein binds to a purine-rich sequence known as the PU-box found near the promoters of target genes and, in coordination with other transcription factors and cofactors, regulates their expression; among the genes are LXR/RXR nuclear receptors34. In the brain, SPI1 is specifically expressed in microglia15. Given SPI1’s control over expression of several downstream genes, this gene may be a major reason enrichment of immune pathways is observed in transcriptomic analysis of human and animal brains. Because of the small fraction of microglia in bulk brain tissue, it is difficult to study the expression of this transcription factor in transcriptomic datasets from whole brains. Some studies using animal models have reported that chronic alcohol consumption can influence the expression of PU.1 in isolated microglia35 and peripheral lung macrophages36,37. However, these studies report the consequences of drinking on PU.1 expression whereas our study uses genomic evidence to demonstrate that regulation of innate immune response likely underlies, at least in part, susceptibility to increased drinking and eventual risk for AUD.
