Frequency of the TREM2 R47H Variant in Various Neurodegenerative Disorders

Abstract

Objective: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer disease (AD), while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort. Methods: We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3058 patients clinically diagnosed with AD, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5089 control subjects. Results: We observed a significant association between the R47H variant and AD, while no association was observed with any other neurodegenerative disease included in this study. Conclusions: Our results support the consensus that the R47H variant is significantly associated with AD. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

The most prevalent rare coding variants of TREM2 conferring risk of Alzheimer's disease: A systematic review and meta‑analysis

“…Finally, a total of 26 datasets from 24 studies ( 4 , 8-12 , 14-16 , 26-40 ) comprising 28,007 cases and 45,121 controls were eligible for the meta-analysis. Among these studies, 24 were for R47H ( 4 , 8-11 , 14-16 , 26-37 , 39 , 40 ), 12 for R62H ( 8 , 9 , 11 , 14-16 , 27 , 28 , 31 , 32 , 38 , 39 ), 11 for D87N ( 8 , 9 , 11 , 15 , 26-28 , 31 , 32 , 36 ) and eight for H157Y ( 8-12 , 26 , 31 , 36 ). A flowchart of the literature search is provided in Fig.…”

“…However, whether it reduces the mRNA and protein expression in humans remains controversial ( 50 ). Furthermore, experiments have revealed that the heterozygous R47H variant may confer a loss of TREM2 function and enhance neuritic dystrophy around plaques, thus increasing the risk of AD ( 51 ), which was ascertained by epidemiological investigations in various populations ( 4 , 8 , 40 ). The R47H variant is enriched in AD cases (1.39%) but less prevalent in cognitively normal controls (0.35%).…”

Investigation of pathology, expression and proteomic profiles in human TREM2 variant postmortem brains with and without Alzheimer’s disease

“…Triggering receptor expressed on myeloid cells 2 (TREM2) was identified as a genetic risk factor for late onset Alzheimer's Disease (AD) with a similar odds ratio to APOE ε4 in 2012, although varying odds ratios have been found in different populations (1,16,18,25,28,33,43,49,52). The frequency of the R47H variant is 0.23-0.25 depending on different reports with an estimated odds ratio of 4.46 for AD which increases to 4.62 in cases with a European descent (2). TREM2 is a 40kD, 230 amino acid transmembrane protein belonging to the immunoglobulin family that is expressed on the plasma membrane of a number of different dendritic cells, including microglia (24,27,42,44).…”

The role of microglia in prion diseases and possible therapeutic targets: a literature review

“…However, when viewed from the perspective of prion disease, TREM2 did not show a contribution to its pathogenesis: there were no significant differences in the disease incubation time or prion titres between the TREM2 −/− , TREM2 −/+ and TREM2 +/+ mice groups, after intracerebral inoculation of Rocky Mountain Laboratories PrP Sc strain (RML6). Also, a study of the relationship between the presence of R47H TREM2 variant – already related to Alzheimer Disease, and an increased risk for sporadic CJD, showed no altered risk for these patients [ 45 , 46 ].…”

“…Recently, a study identified GMR8, a gene that encodes mGlur8 – a protein of the family of metabotropic glutamate receptors -, as a potent risk factor for CJD, being related to the transduction of physiological and cytotoxic signals mediated by PrPC. In this context, carriers of a risk allele in rs6951643 – a variant located in an intronic region of the GRM8 gene – tend to have an increase in mGlur8 expression in microglial cells compared to non-carriers, representing a potent marker for disease risk mapping[ 46 ].…”