In summary, by combining AD survival and endophenotype GWAS analyses, we replicated and discovered multiple genetic loci associated with AAOAAOS. Specifically, we nominate SPI1 as the gene responsible for disease association at the previously reported CELF1 locus. SPI1 encodes PU.1, a transcription factor expressed in microglia and other myeloid cells that directly regulates other AD-associated genes expressed in these cell types. Our data suggest that lower SPI1 expression reduces risk for AD, suggesting a novel therapeutic approach to the treatment of AD. Furthermore, we demonstrate that AAOS-associated SNPs within the MS4A gene cluster are associated with eQTLs in myeloid cells for both MS4A4A and MS4A6A. Specifically, the allele associated with reduced AD risk is associated with lower MS4A4A and MS4A6A expression. This is consistent with the observation that lowering SPI1 expression, which is protective for AD risk, also lowers MS4A4A and MS4A6A expression. These results reinforce the emerging genetic and epigenetic association between AD and a network of microglial expressed genes2,5,17–21, highlighting the need to dissect their functional mechanisms.
