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Nat Neurosci. 2017 Aug;20(8):1052-1061. doi: 10.1038/nn.4587. Epub 2017 Jun 19.

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

Author information

1
Department of Medicine and McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, Missouri, USA.
2
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York,New York, USA.
3
Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York,New York, USA.
4
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
5
Department of Psychiatry, Washington University in St. Louis, Saint Louis, Missouri, USA.
6
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
7
Department of Genetics, Washington University in St. Louis, Saint Louis, Missouri, USA.
8
Department of Neurology, Boston University School of Medicine, Boston, Massachussets, USA.
9
Inserm, U1167, RID-AGE -Risk factors and molecular determinants of aging-related diseases, Lille, France.
10
Univ. Lille - Excellence laboratory Labex DISTALZ, Lille, France.
11
Institut Pasteur de Lille, Lille, France.
12
Icelandic Heart Association, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
13
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
14
Department of Medicine, University of Washington, Seattle, Washington, USA.
15
Department of Biostatistics, Boston University School of Public Health, Boston, Massachussetts, USA.
16
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
17
Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
18
Taub Institute on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, and Department of Neurology, Columbia University, New York,New York, USA.
19
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
20
Department of Ophthalmology, Boston University School of Medicine, Boston, Massachussets, USA.
21
Department of Epidemiology, Boston University School of Public Health, Boston, Massachussetts, USA.
22
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
23
Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA.
24
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA.
25
Centre Hospitalier Universitaire de Lille, U1167, Lille, France.
26
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
27
Department of Biology, Brigham Young University, Provo, Utah, USA.

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.

PMID:
28628103
PMCID:
PMC5759334
DOI:
10.1038/nn.4587
[Indexed for MEDLINE]
Free PMC Article

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