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

Deming, Yuetiva ; Filipello, Fabia ; Cignarella, Francesca ; Cantoni, Claudia ; Hsu, Simon ; Mikesell, Robert ; Li, Zeran ; Del-Aguila, Jorge L. ; Dube, Umber and Farias, Fabiana Geraldo , et al. (2019) In Science Translational Medicine 11(505).
Abstract

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... (More)

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 × 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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Abstract (Swedish)
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 ×... (More)
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 × 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. (Less)
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publication status
published
subject
in
Science Translational Medicine
volume
11
issue
505
article number
eaau2291
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:31413141
  • scopus:85065545662
ISSN
1946-6234
DOI
10.1126/scitranslmed.aau2291
language
English
LU publication?
yes
id
f5813729-fd86-42a2-8c76-13b2d2297648
date added to LUP
2019-09-15 11:45:14
date last changed
2020-01-16 04:05:02
@article{f5813729-fd86-42a2-8c76-13b2d2297648,
  abstract     = {<p>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 × 10<sup>-15</sup>); 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.</p>},
  author       = {Deming, Yuetiva and Filipello, Fabia and Cignarella, Francesca and Cantoni, Claudia and Hsu, Simon and Mikesell, Robert and Li, Zeran and Del-Aguila, Jorge L. and Dube, Umber and Farias, Fabiana Geraldo and Bradley, Joseph and Budde, John and Ibanez, Laura and Fernandez, Maria Victoria and Blennow, Kaj and Zetterberg, Henrik and Heslegrave, Amanda and Johansson, Per M. and Svensson, Johan and Nellgård, Bengt and Lleo, Alberto and Alcolea, Daniel and Clarimon, Jordi and Rami, Lorena and Molinuevo, José Luis and Suárez-Calvet, Marc and Morenas-Rodríguez, Estrella and Kleinberger, Gernot and Ewers, Michael and Harari, Oscar and Haass, Christian and Brett, Thomas J. and Benitez, Bruno A. and Karch, Celeste M. and Piccio, Laura and Cruchaga, Carlos},
  issn         = {1946-6234},
  language     = {eng},
  month        = {08},
  number       = {505},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Translational Medicine},
  title        = {The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk},
  url          = {http://dx.doi.org/10.1126/scitranslmed.aau2291},
  doi          = {10.1126/scitranslmed.aau2291},
  volume       = {11},
  year         = {2019},
}