Dataset Information

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.

SUBMITTER: Ayer AH

PROVIDER: S-EPMC7050643 | biostudies-literature | 2019 Oct-Dec

REPOSITORIES: biostudies-literature

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Frequency of the TREM2 R47H Variant in Various Neurodegenerative Disorders.

Ayer Ariane H AH Wojta Kevin K Ramos Eliana Marisa EM Dokuru Deepika D Chen Jason A JA Karydas Anna M AM Papatriantafyllou John D JD Agiomyrgiannakis Dimitrios D Kamtsadeli Vasiliki V Tsinia Niki N Sali Dimitra D Gylys Karen H KH Agosta Federica F Filippi Massimo M Small Gary W GW Bennett David A DA Gearing Marla M Juncos Jorge L JL Kramer Joel J Lee Suzee E SE Yokoyama Jennifer S JS Mendez Mario F MF Chui Helena H Zarow Chris C Ringman John M JM Kilic Ulkan U Babacan-Yildiz Gülsen G Levey Allan A DeCarli Charles S CS Cotman Carl W CW Boxer Adam L AL Miller Bruce L BL Coppola Giovanni G

Alzheimer disease and associated disorders 20191001 4

<h4>Objective</h4>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.<h4>Methods</h4>We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, in ...[more]

PMID: 31513029

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Project description:ImportanceThe R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders.ObjectiveTo investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases.Design, setting, and participantsThis study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington Alzheimer Disease Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers.Main outcomes and measuresWe assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimer's Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry.ResultsTwelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P = .04) and more frequent α-synucleinopathy. The panmicroglial marker ionized calcium-binding adapter molecule 1 was decreased in all AD cases and the decrease was most pronounced in R47H carriers (mean [SD], in the hilus: 0.114 [0.13] for R47H_AD vs 0.574 [0.26] for control individuals; 2-tailed t test; P = .005 and vs 0.465 [0.32] for AD; P = .02; in frontal cortex gray matter: 0.006 [0.004] for R47H_AD vs 0.016 [0.01] for AD; P = .04 and vs 0.033 [0.013] for control individuals; P < .001). Major histocompatibility complex class II, a marker of microglial activation, was increased in all patients with AD (AD: 2.5, R47H_AD: 2.7, and control: 1.0; P < .01).Conclusions and relevanceOur results demonstrate a complex genetic landscape of LOAD, even in a single pedigree with an apparent autosomal dominant pattern of inheritance. ApoE4, TREM2 R47H, and rare variants in other genes, such as UNC5C D353N, are likely responsible for the notable occurrence of AD in this family. Our findings support the role of the TREM2 receptor in microglial clearance of aggregation-prone proteins that is compromised in R47H carriers and may accelerate the course of disease.

Dataset Information

Frequency of the TREM2 R47H Variant in Various Neurodegenerative Disorders.

Publications

Frequency of the TREM2 R47H Variant in Various Neurodegenerative Disorders.

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