HGNC Approved Gene Symbol: TREM2
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38) : 6:41,158,508-41,163,116 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.1 | {Alzhieimer disease 17, susceptibility to} | 615080 | Autosomal recessive | 3 |
| Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 | 618193 | Autosomal recessive | 3 |
The TREM2 gene encodes a type I transmembrane protein that is a member of the immunoglobulin (Ig) receptor superfamily. It contains an ectodomain, a transmembrane domain, and a short cytoplasmic tail. TREM2 is found on the surface of osteoclasts, immature dendritic cells, and macrophages. In the central nervous system, TREM2 is primarily expressed in microglia (summary by Atagi et al., 2015).
Monocyte/macrophage- and neutrophil-mediated inflammatory responses can be stimulated through a variety of receptors, including G protein-linked 7-transmembrane receptors (e.g., FPR1; 136537), Fc receptors (see 146790), CD14 (158120) and Toll-like receptors (e.g., TLR4; 603030), and cytokine receptors (e.g., IFNGR1; 107470). Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to the Ig superfamily, such as TREM2, or to the C-type lectin superfamily. Depending on their transmembrane and cytoplasmic sequence structure, these receptors have either activating (e.g., KIR2DS1; 604952) or inhibitory functions (e.g., KIR2DL1; 604936). TREM2 is an activating receptor that is expressed on macrophages and dendritic cells (Bouchon et al., 2000).
By searching an EST database with TREM1 (605085) as the probe, Bouchon et al. (2000) identified a cDNA encoding TREM2. The predicted 230-amino acid TREM2 protein was expressed on macrophages and dendritic cells but not on granulocytes or monocytes, suggesting a role for TREM2 in chronic rather than acute inflammatory conditions.
Using flow cytometric analysis, Turnbull et al. (2006) demonstrated that murine Trem2 was expressed on macrophages recruited to peripheral tissues, but not on tissue-resident macrophages, circulating cells, or myeloid progenitors. Il4 (147780) induced expression of Trem2 on resident peritoneal cells.
By genomic sequence analysis, Allcock et al. (2003) determined that all genes in the TREM cluster have an exon encoding the 5-prime UTR and leader peptide, a second exon encoding the IgV domain, and a variable number of downstream exons encoding the stalk, transmembrane, and cytoplasmic regions. TREM2 contains 5 exons. A soluble splice variant of TREM2 lacks exon 4, which encodes the transmembrane region.
By somatic cell hybrid analysis, Bouchon et al. (2000) mapped the TREM1 and TREM2 genes to chromosome 6, where LY95 (604531) is located. By genomic sequence analysis, Allcock et al. (2003) mapped the TREM2 gene to chromosome 6p21.1, within a TREM gene cluster. The mouse Trem2 gene maps to chromosome 17 in a region that shows homology of synteny to human chromosome 6.
TREM2 forms a receptor signaling complex with TYROBP (604142) (Campbell and Colonna, 1999; Bouchon et al., 2001) and triggers activation of the immune responses in macrophages and dendritic cells (Lanier and Bakker, 2000). Patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), in whom mutations in the TYROBP (PLOSL1; 221770) or TREM2 (PLOSL2; 618193) genes have been identified, have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. The data of Paloneva et al. (2002) suggested that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in 2 different subunits of a multisubunit receptor complex result in an identical human disease phenotype.
Paloneva et al. (2003) analyzed differentiation of peripheral blood mononuclear cells from DAP12 (TYROBP)- and TREM2-deficient Finnish or German PLOSL patients into osteoclasts. They found that homozygous loss-of-function mutations in DAP12 or TREM2 resulted in inefficient, aberrant, and delayed differentiation into osteoclasts and significantly diminished bone resorption capability in vitro. RT-PCR analysis detected no differences between patient and control cells in the expression of several genes, but expression of DAP12 and TREM2 increased in control cells during osteoclastic differentiation. Paloneva et al. (2003) concluded that the DAP12-TREM2 signaling complex is important in the differentiation and function of osteoclasts. Independently, Cella et al. (2003) also showed that TREM2-deficient patients have impaired osteoclast differentiation and function.
Bailey et al. (2015) and Atagi et al. (2015) independently identified ApoE (107741) and APOA1 (107680) as binding ligands for TREM2. In vitro studies showed that binding of APOE to TREM2 was associated with increased phagocytosis of apoE-bound apoptotic neurons by primary microglia in a manner that was dependent on TREM2 expression. Expression of the TREM2 variant R47H (rs75932628) dramatically reduced the affinity of APOE for TREM2. The findings established a critical role for TREM2 in regulating the neuroinflammatory environment, and demonstrated a biochemical link between 2 proteins associated with the development of Alzheimer disease (see, e.g., AD17, 615080). Furthermore, Bailey et al. (2015) suggested that the R47H variant may reduce the ability of TREM2+ phagocytes to bind APOE within senile plaques, thereby decreasing the clearance of beta-amyloid (APP; 104760) from the brain.
Schlepckow et al. (2017) determined that TREM2 is shed by proteases of the ADAM family C-terminal to histidine-157, a position where an Alzheimer disease-associated coding variant (H157Y) was discovered in the Han Chinese population (Jiang et al., 2016). Unlike mutations in the Ig-like domain, the H157Y variant within the stalk region leads to enhanced shedding of TREM2. Elevated ectodomain shedding reduces cell surface full-length TREM2 and lowers TREM2-dependent phagocytosis.
Using an unbiased protein microarray screen, Yeh et al. (2016) identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ, 185430 and APOE) as ligands of TREM2. Binding of these ligands by TREM2 was abolished or reduced by Alzheimer disease-associated risk variants (see MOLECULAR GENETICS). Overexpression of wildtype TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, while TREM2 carrying disease-associated variants was impaired in this activity. TREM2-knockout microglia showed reduced internalization of LDL and CLU. Beta-amyloid binds to lipoproteins, and this complex was taken up by microglia in a TREM2-dependent manner.
Crystal Structure
Sudom et al. (2018) reported 3 high-resolution structures for the extracellular ligand-binding domains of R47H mutant TREM2, apolipoprotein-bound wildtype, and phosphatidylserine-bound wildtype TREM2 at 1.8, 2.2, and 2.2 angstroms, respectively. The structures revealed that arg47 plays a critical role in maintaining the structural features of the complementarity-determining region-2 (CDR2) loop and the putative positive ligand-interacting surface (PLIS), stabilizing conformations capable of ligand interaction. Sudom et al. (2018) concluded that, together with in vitro and in vivo characterization, their structural findings elucidated the molecular mechanism underlying loss of ligand binding, putative oligomerization, and functional activity of R47H TREM2.
Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy 2
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a globally distributed recessively inherited disorder leading to death during the fifth decade of life and is characterized by early-onset progressive dementia and bone cysts. Mutations in the TYROBP gene had been shown to cause the disorder (see PLOSL1; 221770), but Paloneva et al. (2002) found that some patients with PLOSL did not have mutations in the TYROBP gene. Paloneva et al. (2002) studied the segregation of marker haplotypes flanking genes that encode polypeptides interacting with TYROBP. The only chromosomal region showing complete segregation to PLOSL was the 6p22-p21 region which includes the TREM2 gene. Mutations in this gene were identified in each of 2 affected families with PLOSL2 (618193), a Swedish and a Norwegian family, and subsequently in 3 other families.
In 6 patients with PLOSL2, including 2 sibs, Klunemann et al. (2005) identified 4 different homozygous mutations in the TREM2 gene (see, e.g., 605086.0006 and 605086.0007).
Susceptibility to Alzheimer Disease 17
In a genomewide association study of 3,550 Icelandic individuals with Alzheimer disease (AD17; 615080) and a large number of controls, Jonsson et al. (2013) found a significant association between the T allele of an R47H (605086.0008) variation in the TREM2 gene (rs75932628) and risk of disease (odds ratio (OR) 2.92, p = 3.42 x 10(-10)). The association was stronger when the controls were older than 85 years. There were 4 homozygous carriers of the variant, 2 of whom were diagnosed with AD. The association was replicated among 2,037 AD cases and 9,727 controls (OR 2.83, p = 0.002).
In an association study of 279 patients with late-onset AD and 346 controls, all from a Chinese southern Han population, Ma et al. (2014) failed to detect the rs75932628T variant.
By high-throughput sequencing of the TREM2 gene in 988 late-onset AD patients and 1,354 healthy controls, all of Han Chinese origin, Jiang et al. (2016) identified 4 rare coding variants and showed that one of these, H157Y (rs22342555), conferred risk of AD in their cohort.
Song et al. (2017) analyzed the AD risk of several TREM2 variants, compared each variant's risk and functional impact by reporter assay, and analyzed expression of TREM2 in human monocytes. Risk analysis was carried out in 1,376 participants (941 affected, 404 unaffected, 31 not determined) from 410 families from the National Institutes of Mental Health (NIMH) Alzheimer's Disease Genetics Initiative Study, and in 10,449 Caucasian cases and controls from the Alzheimer's Disease Sequencing Project (ADSP). The R47H variant had a profound negative effect on signaling in response to most tested lipid ligands, and H157Y demonstrated a lesser defect. Family-based association analysis in the NIMH AD families yielded a p value of .004 for R47H. The H157Y variant was found in 5 of 8 affected individuals and in no unaffected individuals.
In a study using pooled sequencing of 2,082 AD cases and 1,648 cognitively normal elderly controls of European American descent, Jin et al. (2014) identified 16 nonsynonymous variants in the TREM2 gene, of which 2 were significantly associated with disease risk in single variant analysis: R47H (odds ratio (OR) 2.63, p = 0.000917) and R62H (605086.0009) (OR 2.36, p = 0.000236). Additional variants were likely also to confer risk, as the association was still highly significant even after excluding R47H (OR 2.47, p = 0.000000537).
Li et al. (2021) performed a metaanalysis of 26 datasets comprising 28,007 AD cases and 45,121 controls. A significantly increased risk of AD was observed in R47H carriers versus noncarriers (OR 3.88, 95% CI, 3.17-4.76, p less than 0.001), R62H (OR 1.37, 95% CI, 1.11-1.70, p = 0.004), and H157Y (OR 4.22, 95% CI, 1.93-9.21, p less than 0.001). All of these variants are present primarily in individuals of European descent.
In a metaanalysis of 24,808 Alzheimer disease patients and 1,165,514 controls to examine the role of missense variants in TREM2, Stefansson et al. (2024) identified R47H as having an incomplete recessive effect (homozygotes for this variant are at a much greater risk of AD than heterozygotes). Individuals who were compound heterozygous for the R47H and R62H alleles had a higher risk of earlier onset of AD than heterozygotes for either, but much less risk than R47H homozygotes. Stefansson et al. (2024) noted that R47H homozygosity does not contribute to amyloid-beta overproduction but instead disrupts amyloid-beta clearance, leading to the accumulation of amyloid plaques.
Turnbull et al. (2006) found that mice lacking Trem2 were unable to inhibit cytokine production in response to microbial products. There was no difference in cytokine production by macrophages from Trem2-deficient mice and Dap12-deficient mice, leading Turnbull et al. (2006) to conclude that Trem2 is the receptor operative in the increased macrophage cytokine production observed in Dap12-deficient cells. They concluded that TREM2 expressed on newly differentiated and alternatively activated macrophages functions to restrain macrophage activation.
Guerreiro et al. (2013) showed that expression of Trem2 rose in parallel with a rise in cortical levels of beta-amyloid in the TgCRND8 mouse model of Alzheimer disease (AD; 104300). The dysregulation of expression induced by beta-amyloid (A-beta; see 104760) was relatively specific to Trem2, as its partner Tyrobp was not dysregulated.
Using immunohistochemistry, confocal microscopy, RT-PCR, and Western blot analyses, Jay et al. (2015) demonstrated increased expression of Trem2 in Iba1 (AIF1; 601833)-positive myeloid cells surrounding age-related A-beta plaque deposits in brains of 2 transgenic mouse models of AD. Similar expression patterns were observed in 2 neuropathologically confirmed human AD cases. Flow cytometric analysis showed that Trem2-positive macrophages surrounding A-beta deposits in transgenic mouse AD models expressed high levels of Cd45 (151460), a marker for peripherally derived macrophages. Transgenic AD mice lacking Trem2 had reduced A-beta plaque-associated macrophages, inflammation, hippocampal A-beta deposition, astrocytosis, and tau (MAPT; 157140) pathology. Jay et al. (2015) proposed that TREM2 has a role in AD pathology and in neuroinflammation in other central nervous system pathologies.
Filipello et al. (2018) found that Trem2 was selectively expressed by microglial cells in both cortex and hippocampus at different stages of neuronal development in mice. Trem2 -/- mice had fewer microglial cells than wildtype, and the cells became less activated in hippocampus during the early stages of brain development. Whole-cell recording of miniature excitatory postsynaptic currents (mEPSCs) in pyramidal neurons of acute brain slices showed that Trem2 deficiency caused enhanced pre- and postsynaptic contacts and increased electrophysiologic activity. Trem2 -/- microglial cells lacked synapse elimination that occurred through a process requiring cell-to-cell contact. Measurement of engulfment capacity with microglial cells from primary cell culture revealed that Trem2 -/- microglial cells displayed significantly reduced engulfment of synaptosomes compared with wildtype, confirming the role of Trem2 in synapse elimination during brain development. Absence of Trem2 in mice did not compromise the anatomic connections between brain regions, but rather it impaired function, as Trem2 -/- mice displayed an underconnectivity phenotype between prefrontal and hippocampal regions. Trem2 -/- mice exhibited a strong increase in self-grooming and were defective in social behavior.
Using Trem2 -/- mice subjected to a demyelinating cuprizone (CPZ) diet, Nugent et al. (2020) found that Trem2 deficiency prevented conversion from a homeostatic to a disease-associated microglia (DAM) state. Microglia from CPZ-challenged Trem2 -/- mice failed to upregulate lipid metabolism genes. Gene expression changes in microglia from CPZ-challenged Trem2 -/- mice were also present in aged Trem2 -/- microglia and were homogeneous across microglia, leading to neuronal damage during chronic demyelination. Chronic demyelination caused a profound alteration of cholesterol metabolism selectively in Trem2 -/- central nervous system, resulting in accumulated cholesteryl ester (CE) derived from myelin cholesterol in Trem2 -/- brain. This CE accumulation was because Trem2 -/- microglia were able to phagocytose myelin debris during demyelination but were unable to properly metabolize or mediate efflux of myelin lipids. Similar to Trem2 deficiency, Apoe deficiency caused microglial CE accumulation with CPZ. However, Apoe deficiency more broadly affected cholesterol metabolism in brain, as accumulation of CE also occurred in forebrain, glial cells, and cerebral spinal fluid. In vitro analysis showed that Trem2 bound myelin lipids and promoted downstream signaling, and as a result, myelin phagocytosis was impaired in Trem2 -/- cells. Analysis with myelin-treated Trem2-deficient mouse macrophages and human iPSC-derived microglia further revealed that CE accumulation was rescued by ACAT1 (607809) inhibitor and LXR agonist.
In 2 Swedish families, Paloneva et al. (2002) found that members with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL2; 618193) had a homozygous G-to-A transition at position 233 of the TREM2 gene, changing tryptophan-78 to a translation termination codon (W78X).
In a Norwegian family, Paloneva et al. (2002) found that members with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL2; 618193) had a homozygous 558G-T change in the TREM2 gene, resulting in a lys186-to-asn (K186N) substitution.
In an American family that originated from Slovakia that was reported to have polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL2; 618193) by Bird et al. (1983), Paloneva et al. (2002) identified homozygosity for a 401A-G substitution in the TREM2 gene, resulting in an asp134-to-gly (D134G) substitution.
In 2 Italian sibs with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL2; 618193), Paloneva et al. (2002) identified a homozygous mutation in the splice donor consensus site at the second position of exon 3 (482+2T-C) in the TREM2 gene.
In a Bolivian patient with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL2; 618193), Paloneva et al. (2002) identified a homozygous 132G-A mutation in the TREM2 gene, resulting in a trp44-to-ter (W44X) substitution.
In 2 unrelated patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL2; 618193), Klunemann et al. (2005) identified a homozygous 377T-G transversion in exon 2 of the TREM2 gene, resulting in a val126-to-gly (V126G) substitution.
In 2 Belgian sibs with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL2; 618193), Klunemann et al. (2005) identified a homozygous 97C-T transition in exon 2 of the TREM2 gene, resulting in a gln33-to-ter (Q33X) substitution and premature termination of the protein.
By whole-genome analysis of 2,261 Icelandic individuals followed by imputation in 3,550 Alzheimer disease patients and over 100,000 controls, Jonsson et al. (2013) identified a SNP in the TREM2 gene, rs75932628, as significantly associated with Alzheimer disease. The T allele of rs75932628, which encodes an arg47-to-his (R47H) substitution, was found to confer a significant risk of Alzheimer disease in Iceland (OR 2.92, 95% CI, 2.09-4.09, p = 3.42 x 10(-10)). The allele frequency of rs75932628-T in cognitively intact controls 85 years of age or older (0.46%) was significant less than in controls under age 85 years (0.64%).
Stefansson et al. (2024) reported that the allele frequency of the R47H variant ranges from nearly absent (in non-Europeans) to 0.7% among Icelanders and 1.4% among Ashkenazi Jews. In a metaanalysis of 24,808 Alzheimer disease patients and 1,165,514 controls examining the role of missense variants in the TREM2, Stefansson et al. (2024) identified R47H as having an incomplete recessive effect (homozygotes for this variant are at a much greater risk of AD than heterozygotes). Homozygotes for R47H had a high risk (OR 97.1, 95% CI, 23.5-401.1) of developing Alzheimer disease, and at an earlier age than homozygotes for the APOE4 allele (see AD2, 104310). Individuals who were compound heterozygous for the R47H and R62H (605085.0009) alleles had a higher risk of earlier onset of AD than heterozygotes for either, but much less risk than R47H homozygotes. Mean age of onset was 6.4 years earlier among R47H homozygotes than other genotypes in the study.
In a study using pooled sequencing of 2,082 AD cases and 1,648 cognitively normal elderly controls of European American descent, Jin et al. (2014) identified the R62H variant in TREM2 as significantly associated with disease risk in single variant analysis (OR 2.36, p = 0.000236).
Stefansson et al. (2024) reported that the R62H allele confers a minor increased risk of AD in individuals from Iceland, compared with the R47H (605085.0008) allele. Compound heterozygotes for these 2 variants had an earlier age of onset of AD than heterozygotes for either, but still were at much lower risk than R47H homozygotes.
Allcock, R. J. N., Barrow, A. D., Forbes, S., Beck, S., Trowsdale, J. The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44. Europ. J. Immun. 33: 567-577, 2003. [PubMed: 12645956] [Full Text: https://doi.org/10.1002/immu.200310033]
Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeek, C., Zheng, H., Li, X., Rademakers, R., Kang, S. S., Xu, H., Younkin, S., Das, P., Fryer, J. D., Bu, G. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290: 26043-26050, 2015. [PubMed: 26374899] [Full Text: https://doi.org/10.1074/jbc.M115.679043]
Bailey, C. C., DeVaux, L. B., Farzan, M. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J. Biol. Chem. 290: 26033-26042, 2015. [PubMed: 26374897] [Full Text: https://doi.org/10.1074/jbc.M115.677286]
Bird, T. D., Koerker, R. M., Leaird, B. J., Vlcek, B. W., Thorning, D. R. Lipomembranous polycystic osteodysplasia (brain, bone, and fat disease): a genetic cause of presenile dementia. Neurology 33: 81-86, 1983. [PubMed: 6681564] [Full Text: https://doi.org/10.1212/wnl.33.1.81]
Bouchon, A., Dietrich, J., Colonna, M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immun. 164: 4991-4995, 2000. [PubMed: 10799849] [Full Text: https://doi.org/10.4049/jimmunol.164.10.4991]
Bouchon, A., Hernandez-Munain, C., Cella, M., Colonna, M. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J. Exp. Med. 194: 1111-1122, 2001. [PubMed: 11602640] [Full Text: https://doi.org/10.1084/jem.194.8.1111]
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Cella, M., Buonsanti, C., Strader, C., Kondo, T., Salmaggi, A., Colonna, M. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J. Exp. Med. 198: 645-651, 2003. [PubMed: 12913093] [Full Text: https://doi.org/10.1084/jem.20022220]
Filipello, F., Morini, R., Corradini, I., Zerbi, V., Canzi, A., Michalski, B., Erreni, M., Markicevic, M., Starvaggi-Cucuzza, C., Otero, K., Piccio, L., Cignarella, F., and 9 others. The microglial innate immune receptor TREM2 is required for synapse elimination and normal brain connectivity. Immunity 48: 979-991, 2018. [PubMed: 29752066] [Full Text: https://doi.org/10.1016/j.immuni.2018.04.016]
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majournie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., Hazrati, L., Collinge, J., and 12 others. TREM2 variants in Alzheimer's disease. New Eng. J. Med. 368: 117-127, 2013. [PubMed: 23150934] [Full Text: https://doi.org/10.1056/NEJMoa1211851]
Jay, T. R., Miller, C. M., Cheng, P. J., Graham, L. C., Bemiller, S., Broihier, M. L., Xu, G., Margevicius, D., Karlo, J. C., Sousa, G. L., Cotleur, A. C., Butovsky, O., Bekris, L., Staugaitis, S. M., Leverenz, J. B., Pimplikar, S. W., Landreth, G. E., Howell, G. R., Ransohoff, R. M., Lamb, B. T. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J. Exp. Med. 212: 287-295, 2015. [PubMed: 25732305] [Full Text: https://doi.org/10.1084/jem.20142322]
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Klunemann, H. H., Ridha, B. H., Magy, L., Wherrett, J. R., Hemelsoet, D. M., Keen, R. W., De Bleecker, J. L., Rossor, M. N., Marienhagen, J., Klein, H. E., Peltonen, L., Paloneva, J. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64: 1502-1507, 2005. [PubMed: 15883308] [Full Text: https://doi.org/10.1212/01.WNL.0000160304.00003.CA]
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Ma, J., Zhou, Y., Xu, J., Liu, X., Wang, Y., Deng, Y., Wang, G., Xu, W., Ren, R., Liu, X., Zhang, Y., Wang, C., Tang, H., Chen, S. Association study of TREM2 polymorphism rs75932628 with late-onset Alzheimer's disease in Chinese Han population. Neurol. Res. 36: 894-896, 2014. [PubMed: 24725293] [Full Text: https://doi.org/10.1179/1743132814Y.0000000376]
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Paloneva, J., Mandelin, J., Kiialainen, A., Bohling, T., Prudlo, J., Hakola, P., Haltia, M., Konttinen, Y. T., Peltonen, L. DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J. Exp. Med. 198: 669-675, 2003. [PubMed: 12925681] [Full Text: https://doi.org/10.1084/jem.20030027]
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