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The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk

Journal article
Authors Y. Deming
F. Filipello
F. Cignarella
C. Cantoni
S. Hsu
R. Mikesell
Z. R. Li
J. L. Del-Aguila
U. Dube
F. G. Farias
J. Bradley
J. Budde
L. Ibanez
M. V. Fernandez
Kaj Blennow
Henrik Zetterberg
A. Heslegrave
Per Johansson
Johan Svensson
Bengt Nellgård
A. Lleo
D. Alcolea
J. Clarimon
L. Rami
J. L. Molinuevo
M. Suarez-Calvet
E. Morenas-Rodriguez
G. Kleinberger
M. Ewers
O. Harari
C. Haass
T. J. Brett
B. A. Benitez
C. M. Karch
L. Piccio
C. Cruchaga
Published in Science Translational Medicine
Volume 11
Issue 505
ISSN 1946-6234
Publication year 2019
Published at Institute of Clinical Sciences, Department of Anesthesiology and Intensive care
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Language en
Keywords genome-wide association, cerebrospinal-fluid biomarkers, mendelian, randomization, microglial response, susceptibility loci, identification, variants, genotype, metaanalysis, macrophages, Cell Biology, Research & Experimental Medicine
Subject categories Cell biology, Neurochemistry


Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 x 10(-15)); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

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