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TitleTREM2 variants in Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2013
AuthorsGuerreiro, R, Wojtas, A, Bras, J, Carrasquillo, M, Rogaeva, E, Majounie, E, Cruchaga, C, Sassi, C, Kauwe, JSK, Younkin, S, Hazrati, L, Collinge, J, Pocock, J, Lashley, T, Williams, J, Lambert, J-C, Amouyel, P, Goate, A, Rademakers, R, Morgan, K, Powell, J, St George-Hyslop, P, Singleton, A, Hardy, J
Corporate AuthorsAlzheimer Genetic Analysis Group
JournalN Engl J Med
Volume368
Issue2
Pagination117-27
Date Published2013 Jan 10
ISSN1533-4406
KeywordsAged, Alzheimer Disease, Animals, Brain, Exome, Genetic Variation, Genome-Wide Association Study, Genotype, Genotyping Techniques, Heterozygote, Humans, Membrane Glycoproteins, Mice, Mice, Inbred A, Mutation, Receptors, Immunologic, Risk Factors, RNA, Messenger, Sequence Analysis, DNA
Abstract

BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.

METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice.

RESULTS: We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P

CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).

DOI10.1056/NEJMoa1211851
Alternate JournalN. Engl. J. Med.
PubMed ID23150934
PubMed Central IDPMC3631573
Grant List081864 / / Wellcome Trust / United Kingdom
089698 / / Wellcome Trust / United Kingdom
089703 / / Wellcome Trust / United Kingdom
095317 / / Wellcome Trust / United Kingdom
1R01 AG041797-01 / AG / NIA NIH HHS / United States
2P50 AG005681-27 / AG / NIA NIH HHS / United States
5P30 NS069329-02 / NS / NINDS NIH HHS / United States
G0701075 / / Medical Research Council / United Kingdom
G0701441 / / Medical Research Council / United Kingdom
G0802462 / / Medical Research Council / United Kingdom
G0902227 / / Medical Research Council / United Kingdom
G1100695 / / Medical Research Council / United Kingdom
MC_G1000735 / / Medical Research Council / United Kingdom
MC_U123192748 / / Medical Research Council / United Kingdom
P30 NS069329 / NS / NINDS NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
R01 AG018023 / AG / NIA NIH HHS / United States
R01 AG041797 / AG / NIA NIH HHS / United States
R01 AG042611 / AG / NIA NIH HHS / United States
R01 AG18023 / AG / NIA NIH HHS / United States
U01 AG006786 / AG / NIA NIH HHS / United States
U01 AG006786 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
WT089698 / / Wellcome Trust / United Kingdom
Z01 AG000950-10 / AG / NIA NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
/ / Intramural NIH HHS / United States
/ / Medical Research Council / United Kingdom
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Source URL: https://www.j-alz.com/content/trem2-variants-alzheimers-disease