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

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

Deming, Y. (author): Washington University in St. Louis,University of Wisconsin-Madison

Filipello, F. (author): Washington University in St. Louis

Cignarella, F. (author): Washington University in St. Louis

Cantoni, C. (author): Washington University in St. Louis

Hsu, S. (author): Washington University in St. Louis

Mikesell, R. (author): Washington University in St. Louis

Li, Z. R. (author): Washington University in St. Louis

Del-Aguila, J. L. (author): Washington University in St. Louis

Dube, U. (author): Washington University in St. Louis

Farias, F. G. (author): Washington University in St. Louis

Bradley, J. (author): Washington University in St. Louis

Budde, J. (author): Washington University in St. Louis

Ibanez, L. (author): Washington University in St. Louis

Fernandez, M. V. (author): Washington University in St. Louis

Blennow, Kaj, 1958 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry,Sahlgrenska University Hospital,Sahlgrenska Academy

Zetterberg, Henrik, 1973 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry,Sahlgrenska University Hospital,University College London,Sahlgrenska Academy

Heslegrave, A. (author): University College London

Johansson, Per, 1966 (author): Lund University,Lunds universitet,Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition,Kliniska Vetenskaper, Helsingborg,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Clinical Sciences, Helsingborg,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine

Svensson, Johan, 1964 (author): Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition,Sahlgrenska Academy

Nellgård, Bengt, 1956 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för anestesiologi och intensivvård,Institute of Clinical Sciences, Department of Anesthesiology and Intensive care,Sahlgrenska Academy,Sahlgrenska University Hospital

Lleo, A. (author): Autonomous University of Barcelona,CIBER Enfermedades Neurodegenerativas (CIBERNED)

Alcolea, D. (author): Autonomous University of Barcelona,CIBER Enfermedades Neurodegenerativas (CIBERNED)

Clarimon, J. (author): CIBER Enfermedades Neurodegenerativas (CIBERNED),Autonomous University of Barcelona

Rami, L. (author): Hospital Clínic of Barcelona

Molinuevo, J. L. (author): Pasqual Maragall Foundation for Research on Alzheimer,Hospital Clínic of Barcelona

Suarez-Calvet, M. (author): German Center for Neurodegenerative Diseases (DZNE), Bonn,World Orthopaedic Concern,Pasqual Maragall Foundation for Research on Alzheimer

Morenas-Rodriguez, E. (author): Munich Cluster for Systems Neurology,World Orthopaedic Concern

Kleinberger, G. (author): Munich Cluster for Systems Neurology,ISAR Bioscience GmbH,Ludwig-Maximilian University of Munich

Ewers, M. (author): University Hospital Munich

Harari, O. (author): Washington University in St. Louis

Haass, C. (author): Munich Cluster for Systems Neurology,Ludwig-Maximilian University of Munich,German Center for Neurodegenerative Diseases (DZNE), Bonn

Brett, T. J. (author): Washington University in St. Louis

Benitez, B. A. (author): Washington University in St. Louis

Karch, C. M. (author): Washington University in St. Louis

Piccio, L. (author): Washington University in St. Louis,University of Sydney

Cruchaga, C. (author)

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Washington University in St Louis University of Wisconsin-Madison (creator_code:org_t)

American Association for the Advancement of Science (AAAS), 2019
2019
English.
In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:505

Related links:: https://www.ncbi.nlm...; show more...; http://dx.doi.org/10...; https://gup.ub.gu.se...; https://doi.org/10.1...; https://lup.lub.lu.s...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)

Keyword

genome-wide association
cerebrospinal-fluid biomarkers
mendelian
randomization
microglial response
susceptibility loci
identification
variants
genotype
metaanalysis
macrophages
Cell Biology
Research & Experimental Medicine

Publication and Content Type

ref (subject category)
art (subject category)

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

Articles in the publication: Science Translat ...

By the university: University of Gothenburg; Lund University

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