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Publication : A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease.

First Author  Huang KL Year  2017
Journal  Nat Neurosci Volume  20
Issue  8 Pages  1052-1061
PubMed ID  28628103 Mgi Jnum  J:249136
Mgi Id  MGI:6093262 Doi  10.1038/nn.4587
Citation  Huang KL, et al. (2017) A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease. Nat Neurosci 20(8):1052-1061
abstractText  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 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 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 was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected 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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