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

Kuan Lin Huang, Edoardo Marcora, Anna A. Pimenova, Antonio F. Di Narzo, Manav Kapoor, Sheng Chih Jin, Oscar Harari, Sarah Bertelsen, Benjamin P. Fairfax, Jake Czajkowski, Vincent Chouraki, Benjamin Grenier-Boley, Céline Bellenguez, Yuetiva Deming, Andrew McKenzie, Towfique Raj, Alan E. Renton, John Budde, Albert Smith, Annette FitzpatrickJoshua C. Bis, Anita DeStefano, Hieab H.H. Adams, M. Arfan Ikram, Sven Van Der Lee, Jorge L. Del-Aguila, Maria Victoria Fernandez, Laura Ibañez, Rebecca Sims, Valentina Escott-Price, Richard Mayeux, Jonathan L. Haines, Lindsay A. Farrer, Margaret A. Pericak-Vance, Jean Charles Lambert, Cornelia Van Duijn, Lenore Launer, Sudha Seshadri, Julie Williams, Philippe Amouyel, Gerard D. Schellenberg, Bin Zhang, Ingrid Borecki, John S.K. Kauwe, Carlos Cruchaga, Ke Hao, Alison M. Goate

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1052-1061
Number of pages10
JournalNature Neuroscience
Volume20
Issue number8
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Neuroscience(all)

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