Title | TREM2 variants in Alzheimer's disease. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Guerreiro, 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 Authors | Alzheimer Genetic Analysis Group |
Journal | N Engl J Med |
Volume | 368 |
Issue | 2 |
Pagination | 117-27 |
Date Published | 2013 Jan 10 |
ISSN | 1533-4406 |
Keywords | Aged, 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.). |
DOI | 10.1056/NEJMoa1211851 |
Alternate Journal | N. Engl. J. Med. |
PubMed ID | 23150934 |
PubMed Central ID | PMC3631573 |
Grant List | 081864 / / 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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