MS4A Alzheimer’s Risk Gene Linked to TREM2 Signaling

Searching the whole genome for variants that associate with soluble TREM2 in human cerebrospinal fluid, researchers have turned up single-nucleotide polymorphisms near genes for the membrane-spanning 4-domains subfamily A, which had been linked previously to late-onset AD.

Two common SNPs in the MS4A gene cluster stood out. An intergenic variant that lowers AD risk and delays symptom onset promotes expression of MS4A4A and MS4A6A. This variant associates with higher CSF sTREM2. In keeping with the theme, a missense mutation in the MS4A4A gene seems to do the opposite. It increases disease risk and accelerates onset, while reducing sTREM2. Detailed in a paper posted on June 20 to the bioRχiv preprint server, the analysis suggests that MS4A family members regulate processing of the microglial receptor.

“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,” wrote the scientists, who were led by Celeste Karch, Laura Piccio, and Carlos Cruchaga, all from Washington University, St. Louis.

Prior GWAS indicated that variants in MS4A4E and MS4A6A increased and decreased, respectively, AD risk by about 10 percent (Hollingworth et al., 2011; Naj et al., 2011). The roughly 16 members of the MS4A transmembrane family are thought to have a function in lipid sensing on membranes and to regulate protein trafficking in microglia; however, a mechanistic explanation for their AD association had not been established.

Joint first authors Yuetiva Deming, Fabia Filipello, and Francesca Cignarella set out to identify genetic modifiers of CSF sTREM2, which ticks higher in early AD and correlates with CSF tau and phospho-tau (Mar 2016 news). Researchers believe levels of this soluble fragment of the microglial receptor reflect activation of the cells.

Deming and colleagues ran a genome-wide association analysis of sTREM2 levels among 813 people in the Alzheimer’s Disease Neuroimaging Initiative. People with TREM2 variants that predispose to AD were excluded. From more than 7.3 million common SNPs, a positive signal shot up in chromosome 11q12, the site of the MS4A cluster. Lying near MS4A4A, the intergenic SNP rs1582763 emerged as most significant. It associated with higher sTREM2, accounting for more than 6 percent of the sTREM2 variance. The association held among 606 AD cases and 207 normal controls. Previous GWAS had indicated this SNP reduced AD risk and delayed disease onset (Lambert et al., 2013; Huang et al., 2017). 

Controlling for this association, Deming and colleagues reanalyzed the data to discover that another polymorphism, rs659156, independently associated with sTREM2, but this time with lower levels of the fragment. This SNP switches a valine for a methionine at position 159 of the MS4A4A protein and associates with increased risk for AD and with accelerated onset. The authors replicated both associations with an additional 580 CSF samples from six different sources: the Knight ADRC center at WashU; the DIAN cohort; two studies from the University of Gothenburg; one from Saint Pau Hospital, Barcelona; and one at the Clinic Institute of Neurosciences, Hospital Clinic of Barcelona.

Together, the findings suggest these SNPs modulate expression of MS4A family members and, by extension, processing of TREM2. In line with this, Deming and colleagues found that rs1582763 correlated with expression of MS4A6A in the blood, and to a lesser extent expression of MS4A4A and MS4A2. The rs659156 missense variant correlated with MS4A4A and MS4A6A in the blood. Further, in 103 brain samples from the Knight ADRC center and 19 samples from DIAN, expression of the MS4A family members 6A, 4A, and 7 correlated with expression of TREM2. In autopsy-confirmed late-onset AD samples and controls, the correlation between TREM2 expression and MS4A4A/MS4A6A was particularly strong.

Drilling deeper, the authors found that MS4A4A co-localized with TREM2 in the cytoplasm of human macrophages, mainly near the nucleus and less so on the plasma membrane. Two antibodies against MS4A4A suppressed interleukin-4-induced release of sTREM2 into the cell medium, supporting the idea that MS4A4A, a transmembrane protein, promotes TREM2 processing. One antibody to MS4A6A had no effect in this assay, but the authors noted that they can’t yet rule out the possibility that it may also be involved.

The authors believe MS4A4A could eventually become a therapeutic target, but caution that more work will be needed to understand how this protein affects sTREM2. Little is known about MSA4A proteins in the brain. A previous study by Robert Datta at Harvard Medical School on the MS4A protein family in the mammalian olfactory system identified them as seven-transmembrane G-protein-coupled receptors (GPCRs) that responded to fatty acid ligands (Greer et al., 2016). 

As of July 6, the manuscript pdf has been viewed on bioRχiv 109 times, the abstract 444 times.—Tom Fagan

Comments

  1. 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.

    View all comments by Ekaterina Rogaeva

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References

News Citations

  1. Microglial Marker TREM2 Rises in Early Alzheimer’s and on Western Diet

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External Citations

  1. MS4A4E 
  2. MS4A6A

Further Reading

No Available Further Reading

Primary Papers

  1. 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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