Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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, Mayeux, Richard, Haines, Jonathan L, Farrer, Lindsay A, Pericak-Vance, Margaret A, Lambert, Jean Charles, van Duijn, Cornelia, Launer, Lenore, Seshadri, Sudha, Williams, Julie, 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

[img]
Preview
PDF - Accepted Post-Print Version
Download (550kB) | Preview

Abstract

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: Published Online
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Publisher: Nature Publishing Group
ISSN: 1097-6256
Date of First Compliant Deposit: 4 January 2018
Date of Acceptance: 20 May 2017
Last Modified: 07 Jan 2018 05:39
URI: http://orca.cf.ac.uk/id/eprint/107886

Citation Data

Cited 69 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics