TREM2 variants in Alzheimer's disease
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TREM2 variants in Alzheimer's disease. / Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S K; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St George-Hyslop, Peter; Singleton, Andrew; Hardy, John; Alzheimer Genetic Analysis Group.
in: NEW ENGL J MED, Jahrgang 368, Nr. 2, 10.01.2013, S. 117-27.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - TREM2 variants in Alzheimer's disease
AU - Guerreiro, Rita
AU - Wojtas, Aleksandra
AU - Bras, Jose
AU - Carrasquillo, Minerva
AU - Rogaeva, Ekaterina
AU - Majounie, Elisa
AU - Cruchaga, Carlos
AU - Sassi, Celeste
AU - Kauwe, John S K
AU - Younkin, Steven
AU - Hazrati, Lilinaz
AU - Collinge, John
AU - Pocock, Jennifer
AU - Lashley, Tammaryn
AU - Williams, Julie
AU - Lambert, Jean-Charles
AU - Amouyel, Philippe
AU - Goate, Alison
AU - Rademakers, Rosa
AU - Morgan, Kevin
AU - Powell, John
AU - St George-Hyslop, Peter
AU - Singleton, Andrew
AU - Hardy, John
AU - Alzheimer Genetic Analysis Group
AU - Bussche van den, Hendrik
PY - 2013/1/10
Y1 - 2013/1/10
N2 - 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<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.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.).
AB - 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<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.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.).
KW - Aged
KW - Alzheimer Disease
KW - Animals
KW - Brain
KW - Exome
KW - Genetic Variation
KW - Genome-Wide Association Study
KW - Genotype
KW - Genotyping Techniques
KW - Heterozygote
KW - Humans
KW - Membrane Glycoproteins
KW - Mice
KW - Mice, Inbred A
KW - Mutation
KW - RNA, Messenger
KW - Receptors, Immunologic
KW - Risk Factors
KW - Sequence Analysis, DNA
U2 - 10.1056/NEJMoa1211851
DO - 10.1056/NEJMoa1211851
M3 - SCORING: Journal article
C2 - 23150934
VL - 368
SP - 117
EP - 127
JO - NEW ENGL J MED
JF - NEW ENGL J MED
SN - 0028-4793
IS - 2
ER -