A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease
Anna A Pimenova,
Antonio F. Di Narzo,
Sheng Chih Jin,
Benjamin P Fairfax,
Alan E Renton,
Joshua C Bis,
Hieab HH Adams,
M. Arfan Ikram,
Sven van der Lee,
Jorge L Del-Aguila,
Maria Victoria Fernandez,
The International Genomics of Alzheimer’s Project,
The Alzheimer’s Disease Neuroimaging Initiative,
Jonathan L. Haines,
Lindsay A. Farrer,
A. J. Griswold,
Jean Charles Lambert,
Cornelia van Duijn,
Gerard D. Schellenberg,
John S. K. Kauwe,
Alison M. Goate
Posted 26 Feb 2017
bioRxiv DOI: 10.1101/110957 (published DOI: 10.1038/nn.4587)
Posted 26 Feb 2017
A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and fourteen novel loci associated with age at onset. LD score regression of 220 cell types implicated regulation of myeloid gene expression in AD risk. In particular, the minor allele of rs1057233 (G), within the previously reported CELFI AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell?development and function. AD heritability is enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affect the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.
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