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

TitleThe MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk.
Publication TypeJournal Article
Year of Publication2019
AuthorsDeming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, Li Z, Del-Aguila JL, Dube U, Farias FGeraldo, Bradley J, Budde J, Ibañez L, Fernández MVictoria, Blennow K, Zetterberg H, Heslegrave A, Johansson PM, Svensson J, Nellgård B, Lleó A, Alcolea D, Clarimón J, Rami L, Molinuevo JLuis, Suárez-Calvet M, Morenas-Rodríguez E, Kleinberger G, Ewers M, Harari O, Haass C, Brett TJ, Benitez BA, Karch CM, Piccio L, Cruchaga C
JournalSci Transl Med
Volume11
Issue505
Date Published2019 Aug 14
ISSN1946-6242
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 () gene region were associated with CSF sTREM2 concentrations (rs1582763; = 1.15 × 10); 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 and 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 overexpression, and that silencing of 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 locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in risk-variant carriers but also in those with sporadic disease.

DOI10.1126/scitranslmed.aau2291
Alternate JournalSci Transl Med
PubMed ID31413141
PubMed Central IDPMC6697053
Grant ListR01 AG057777 / AG / NIA NIH HHS / United States
RF1 AG058501 / AG / NIA NIH HHS / United States
R01 HL119813 / HL / NHLBI NIH HHS / United States
U01 AG058922 / AG / NIA NIH HHS / United States
R01 AG044546 / AG / NIA NIH HHS / United States
RF1 AG053303 / AG / NIA NIH HHS / United States