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Sci Transl Med. 2017 Dec 20;9(421). pii: eaai7635. doi: 10.1126/scitranslmed.aai7635.

A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants.

Ryan KJ1,2,3,4, White CC1,2,4, Patel K1,2,3,4, Xu J1,2,4, Olah M4,5, Replogle JM1,2,3,4, Frangieh M1,2,4, Cimpean M1,2,4, Winn P1,2,4, McHenry A1,2,4, Kaskow BJ1,2,3,4, Chan G1,2,3,4, Cuerdon N1,2,3,4, Bennett DA6, Boyd JD1,3, Imitola J7, Elyaman W4,5, De Jager PL4,5, Bradshaw EM8,5.

Author information

1
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB168, Boston, MA 02115, USA.
3
Harvard Medical School, Boston, MA 02115, USA.
4
Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
5
Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA.
6
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
7
Laboratory of Neural Stem Cells and Functional Neurogenetics, Departments of Neurology and Neuroscience, The Ohio State University College of Medicine, 333 West 10th Avenue, Columbus, OH 43210, USA.
8
Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA. emb2280@cumc.columbia.edu.

Abstract

Microglia are emerging as a key cell type in neurodegenerative diseases, yet human microglia are challenging to study in vitro. We developed an in vitro cell model system composed of human monocyte-derived microglia-like (MDMi) cells that recapitulated key aspects of microglia phenotype and function. We then used this model system to perform an expression quantitative trait locus (eQTL) study examining 94 genes from loci associated with Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We found six loci (CD33, PILRB, NUP160, LRRK2, RGS1, and METTL21B) in which the risk haplotype drives the association with both disease susceptibility and altered expression of a nearby gene (cis-eQTL). In the PILRB and LRRK2 loci, the cis-eQTL was found in the MDMi cells but not in human peripheral blood monocytes, suggesting that differentiation of monocytes into microglia-like cells led to the acquisition of a cellular state that could reveal the functional consequences of certain genetic variants. We further validated the effect of risk haplotypes at the protein level for PILRB and CD33, and we confirmed that the CD33 risk haplotype altered phagocytosis by the MDMi cells. We propose that increased LRRK2 gene expression by MDMi cells could be a functional outcome of rs76904798, a single-nucleotide polymorphism in the LRKK2 locus that is associated with Parkinson's disease.

PMID:
29263232
PMCID:
PMC5945290
DOI:
10.1126/scitranslmed.aai7635
[Indexed for MEDLINE]
Free PMC Article

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