| Literature DB >> 28628103 |
Kuan-Lin Huang1, Edoardo Marcora2,3, Anna A Pimenova3, Antonio F Di Narzo2, Manav Kapoor2,3, Sheng Chih Jin4, Oscar Harari5, Sarah Bertelsen3, Benjamin P Fairfax6, Jake Czajkowski7, Vincent Chouraki8, Benjamin Grenier-Boley9,10,11, Céline Bellenguez9,10,11, Yuetiva Deming5, Andrew McKenzie2, Towfique Raj2,3, Alan E Renton3, John Budde5, Albert Smith12, Annette Fitzpatrick13, Joshua C Bis14, Anita DeStefano15, Hieab H H Adams16, M Arfan Ikram16, Sven van der Lee16, Jorge L Del-Aguila5, Maria Victoria Fernandez5, Laura Ibañez5, Rebecca Sims17, Valentina Escott-Price17, Richard Mayeux18, Jonathan L Haines19, Lindsay A Farrer15,20,21,22, Margaret A Pericak-Vance22,23, Jean Charles Lambert9,10,11, Cornelia van Duijn16, Lenore Launer24, Sudha Seshadri8, Julie Williams17, Philippe Amouyel9,10,11,25, Gerard D Schellenberg26, Bin Zhang2, Ingrid Borecki7, John S K Kauwe27, Carlos Cruchaga5, Ke Hao2, Alison M Goate2,3.
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.Entities:
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Year: 2017 PMID： 28628103 PMCID： PMC5759334 DOI： 10.1038/nn.4587
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884