PT - JOURNAL ARTICLE AU - Kuan-lin Huang AU - Edoardo Marcora AU - Anna A Pimenova AU - Antonio F Di Narzo AU - Manav Kapoor AU - Sheng Chih Jin AU - Oscar Harari AU - Sarah Bertelsen AU - Benjamin P Fairfax AU - Jake Czajkowski AU - Vincent Chouraki AU - Benjamin Grenier-Boley AU - Céline Bellenguez AU - Yuetiva Deming AU - Andrew McKenzie AU - Towfique Raj AU - Alan E Renton AU - John Budde AU - Albert Smith AU - Annette Fitzpatrick AU - Joshua C Bis AU - Anita DeStefano AU - Hieab HH Adams AU - M Arfan Ikram AU - Sven van der Lee AU - Jorge L. Del-Aguila AU - Maria Victoria Fernandez AU - Laura Ibañez AU - The International Genomics of Alzheimer's Project, The Alzheimer’s Disease Neuroimaging Initiative AU - Rebecca Sims AU - Valentina Escott-Price AU - Richard Mayeux AU - Jonathan L Haines AU - Lindsay A Farrer AU - Margaret A. Pericak-Vance AU - Jean Charles Lambert AU - Cornelia van Duijn AU - Lenore Launer AU - Sudha Seshadri AU - Julie Williams AU - Philippe Amouyel AU - Gerard D Schellenberg AU - Bin Zhang AU - Ingrid Borecki AU - John S K Kauwe AU - Carlos Cruchaga AU - Ke Hao AU - Alison M Goate TI - A common haplotype lowers <em>SPI1</em> (PU.1) expression in myeloid cells and delays age at onset for Alzheimer’s disease AID - 10.1101/110957 DP - 2017 Jan 01 TA - bioRxiv PG - 110957 4099 - http://biorxiv.org/content/early/2017/02/26/110957.short 4100 - http://biorxiv.org/content/early/2017/02/26/110957.full AB - In this study we used age at onset of Alzheimer’s disease (AD), cerebrospinal fluid (CSF) biomarkers, and eQTL datasets to fine map AD-associated GWAS loci and investigate the underlying mechanisms. In a genome-wide survival analysis of 40,255 samples, eight of the previously reported AD risk loci are significantly (p &lt; 5×10−8) or suggestively (p &lt; 1×10−5) associated with age at onset-defined survival and a further fourteen novel loci reached suggestive significance. One third (8/22) of these SNPs are cis-eQTLs in monocytes and/or macrophages, including rs7930318 associated with expression of MS4A4A and MS4A6A. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, shows association with higher age at onset of AD (p=8.40×10−6), higher CSF levels of Aβ42 (p=1.2×10−4), and lower expression of SPI1 in monocytes (p = 1.50×10−105) and macrophages (p = 6.41×10−87). SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the SPI1 cistromes of monocytes and macrophages, implicating a myeloid PU.1 target gene network in the etiology of AD. Finally, experimentally altered PU.1 levels are correlated with phagocytic activity of BV2 mouse microglial cells and specific changes in the expression of multiple myeloid-expressed genes, including the mouse orthologs of AD risk genes, MS4A4A and MS4A6A. Our results collectively suggest that lower SPI1 expression reduces AD risk by modulating myeloid cell gene expression and function.