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

TitleA common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2017
AuthorsHuang K-L, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SChih, Harari O, Bertelsen S, Fairfax BP, Czajkowski J, Chouraki V, Grenier-Boley B, Bellenguez C, Deming Y, McKenzie A, Raj T, Renton AE, Budde J, Smith A, Fitzpatrick A, Bis JC, DeStefano A, Adams HHH, M Ikram A, van der Lee S, Del-Aguila JL, Fernández MVictoria, Ibañez L, Sims R, Escott-Price V, Mayeux R, Haines JL, Farrer LA, Pericak-Vance MA, Lambert JCharles, van Duijn C, Launer L, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Zhang B, Borecki I, Kauwe JSK, Cruchaga C, Hao K, Goate AM
Corporate AuthorsInternational Genomics of Alzheimer's Project, Alzheimer's Disease Neuroimaging Initiative
JournalNat Neurosci
Volume20
Issue8
Pagination1052-1061
Date Published2017 Aug
ISSN1546-1726
KeywordsAlleles, Alzheimer Disease, Animals, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, Linkage Disequilibrium, Male, Mice, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins, Risk Factors, Trans-Activators, Transcription Factors
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.

DOI10.1038/nn.4587
Alternate JournalNat. Neurosci.
PubMed ID28628103
PubMed Central IDPMC5759334
Grant ListR01 AG044546 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U01 AG052411 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
RF1 AG053303 / AG / NIA NIH HHS / United States
RF1 AG054011 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
U01 AG049508 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
/ / Wellcome Trust / United Kingdom
R25 DA027995 / DA / NIDA NIH HHS / United States
Z99 AG999999 / / Intramural NIH HHS / United States
MR/L010305/1 / / Medical Research Council / United Kingdom
R01 AG035083 / AG / NIA NIH HHS / United States