RT Journal Article
SR Electronic
T1 The <em>MS4A</em> gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 352179
DO 10.1101/352179
A1 Yuetiva Deming
A1 Fabia Filipello
A1 Francesca Cignarella
A1 Claudia Cantoni
A1 Simon Hsu
A1 Robert Mikesell
A1 Zeran Li
A1 Jorge L Del-Aguila
A1 Umber Dube
A1 Fabiana Geraldo Farias
A1 Joseph Bradley
A1 Bruno Benitez
A1 John Budde
A1 Laura Ibanez
A1 Maria Victoria Fernandez
A1 Alzheimer’s Disease Neuroimaging Initiative (ADNI)
A1 Dominantly Inherited Alzheimer Network (DIAN)
A1 Kaj Blennow
A1 Henrik Zetterberg
A1 Amanda Heslegrave
A1 Per M Johansson
A1 Johan Svensson
A1 Bengt Nellgård
A1 Alberto Lleo
A1 Daniel Alcolea
A1 Jordi Clarimon
A1 Lorena Rami
A1 José Luis Molinuevo
A1 Marc Suarez-Calvet
A1 Estrella Morenas-Rodríguez
A1 Gernot Kleinberger
A1 Michael Ewers
A1 Oscar Harari
A1 Christian Haass
A1 Thomas J Brett
A1 Celeste M. Karch
A1 Laura Piccio
A1 Carlos Cruchaga
YR 2018
UL http://biorxiv.org/content/early/2018/06/20/352179.abstract
AB Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with Alzheimer disease (AD) status. 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 help reveal biological mechanisms underlying AD and identify novel therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 levels. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with higher CSF sTREM2 levels (rs1582763; P = 1.15×10−15) and replicated in independent datasets. The variants associated with increased levels of sTREM2 are also associated with reduced AD risk and delayed age-at-onset. Rs1582763 influences expression of MS4A4A and MS4A6A in multiple tissues, suggesting that one or both of these genes are important for regulating sTREM2. MS4A genes encode transmembrane proteins that may play a role in intracellular protein trafficking in microglia. We used human macrophages to begin to test the relationship between MS4A4A and TREM2 and found that they co-localize intracellularly and that antibody-mediated targeting of MS4A4A reduces sTREM2. Thus, genetic, molecular, and cellular findings suggest that MS4A4A regulates sTREM2. These findings also provide a mechanistic explanation of the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 is involved in sporadic AD risk in general, not only in TREM2 risk-variant carriers.