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

Huang, Kuan-lin, Marcora, Edoardo, Pimenova, Anna A., Di Narzo, Antonio F., Kapoor, Manav, Jin, Sheng Chih, Harari, Oscar, Bertelsen, Sarah, Fairfax, Benjamin P., Czajkowski, Jake, Chouraki, Vincent, Grenier-Boley, Benjamin, Bellenguez, Céline, Deming, Yuetiva, McKenzie, Andrew, Raj, Towfique, Renton, Alan E., Budde, John, Smith, Albert, Fitzpatrick, Annette, Bis, Joshua C., DeStefano, Anita, Adams, Hieab H. H., Ikram, M. Arfan, van der Lee, Sven, Del-Aguila, Jorge L., Fernandez, Maria Victoria, Ibañez, Laura, Sims, Rebecca, Escott-Price, Valentina ORCID:, Mayeux, Richard, Haines, Jonathan L., Farrer, Lindsay A., Pericak-Vance, Margaret A., Lambert, Jean Charles, van Duijn, Cornelia, Launer, Lenore, Seshadri, Sudha, Williams, Julie ORCID:, Amouyel, Philippe, Schellenberg, Gerard D., Zhang, Bin, Borecki, Ingrid, Kauwe, John S. K., Cruchaga, Carlos, Hao, Ke and Goate, Alison M. 2017. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease. Nature Neuroscience 20 (8) , pp. 1052-1061. 10.1038/nn.4587

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: The International Genomics of Alzheimer's Project, The Alzheimer's Disease Neuroimaging Initiative,
Publisher: Nature Publishing Group
ISSN: 1097-6256
Date of First Compliant Deposit: 4 January 2018
Date of Acceptance: 20 May 2017
Last Modified: 12 Nov 2023 19:07

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