A common haplotype lowers SPI1 (PU.1) expression in myeloid cells and delays age at onset for Alzheimer’s disease
Abstract
In this study we used age at onset of Alzheimer’s disease (AD), cerebrospinal fluid (CSF) biomarkers, and eQTL datasets to fine map AD-associated GWAS loci and investigate the underlying mechanisms. In a genome-wide survival analysis of 40,255 samples, eight of the previously reported AD risk loci are significantly (p < 5×10−8) or suggestively (p < 1×10−5) associated with age at onset-defined survival and a further fourteen novel loci reached suggestive significance. One third (8/22) of these SNPs are cis-eQTLs in monocytes and/or macrophages, including rs7930318 associated with expression of MS4A4A and MS4A6A. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, shows association with higher age at onset of AD (p=8.40×10−6), higher CSF levels of Aβ42 (p=1.2×10−4), and lower expression of SPI1 in monocytes (p = 1.50×10−105) and macrophages (p = 6.41×10−87). SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the SPI1 cistromes of monocytes and macrophages, implicating a myeloid PU.1 target gene network in the etiology of AD. Finally, experimentally altered PU.1 levels are correlated with phagocytic activity of BV2 mouse microglial cells and specific changes in the expression of multiple myeloid-expressed genes, including the mouse orthologs of AD risk genes, MS4A4A and MS4A6A. Our results collectively suggest that lower SPI1 expression reduces AD risk by modulating myeloid cell gene expression and function.
Footnotes
↵# Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at:http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
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