Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, Li Z, Del-Aguila JL, Dube U, Farias FG, Bradley J, Budde J, Ibanez L, Fernandez MV, Blennow K, Zetterberg H, Heslegrave A, Johansson PM, Svensson J, Nellgård B, Lleo A, Alcolea D, Clarimon J, Rami L, Molinuevo JL, Suárez-Calvet M, Morenas-Rodríguez E, Kleinberger G, Ewers M, Harari O, Haass C, Brett TJ, Benitez BA, Karch CM, Piccio L, Cruchaga C. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk. Sci Transl Med. 2019 Aug 14;11(505) PubMed.
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University of Toronto
This reported interesting findings that common variants in the MS4A gene-family region are reproducibly associated with sTREM2 levels in the CSF of both AD cases and controls. It would be important to understand the dynamic of such an association, keeping in mind that sTREM2 levels are not steady. For instance, the Dominantly Inherited Alzheimer Network study reported that CSF sTREM2 increased in carriers of autosomal dominant AD mutations five years before expected symptom onset (Suarez-Calvet et al, 2016). Intriguingly, Deming et al., detected two independent association signals (elevated sTREM2 levels are linked to rs1582763, while rs6591561 is associated with reduced sTREM2 levels).
Both MS4A and TREM are known AD loci containing a cluster of homologous genes within high linkage disequilibrium blocks, and should be thoroughly investigated for the presence of potentially functional variations. Previously, we conducted next-generation sequencing of 15 genes within the MS4A and TREM gene-clusters (Ghani et al., 2016). Even in our modest data set we observed significant enrichment of TREM2 damaging missense substitutions in cases vs controls.
Surprisingly, investigation of the MS4A gene-cluster revealed that damaging variants were twice as frequent in controls than cases. Validation of our observation in large data sets might address the question of whether such variants could contribute to the protective effect of the minor alleles of GWAS-significant SNPs at the MS4A locus, as well as their link to sTREM2 levels.
References:
Suárez-Calvet M, Araque Caballero MÁ, Kleinberger G, Bateman RJ, Fagan AM, Morris JC, Levin J, Danek A, Ewers M, Haass C, Dominantly Inherited Alzheimer Network. Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury. Sci Transl Med. 2016 Dec 14;8(369):369ra178. PubMed.
Ghani M, Sato C, Kakhki EG, Gibbs JR, Traynor B, St George-Hyslop P, Rogaeva E. Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set. Neurobiol Aging. 2016 Jun;42:217.e7-217.e13. Epub 2016 Mar 21 PubMed.
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