• Rita Guerreiro, Aleksandra Wojtas, Jose Bras, Minerva Carrasquillo, Ekaterina Rogaeva, Elisa Majounie, Carlos Cruchaga, Celeste Sassi, John S K Kauwe, Steven Younkin, Lilinaz Hazrati, John Collinge, Jennifer Pocock, Tammaryn Lashley, Julie Williams, Jean-Charles Lambert, Philippe Amouyel, Alison Goate, Rosa Rademakers, Kevin Morgan, John Powell, Peter St George-Hyslop, Andrew Singleton, John Hardy, and Alzheimer Genetic Analysis Group.
• University College London (UCL) Institute of Neurology, London, United Kingdom.
• N. Engl. J. Med. 2013 Jan 10; 368 (2): 117127117-27.

BackgroundHomozygous 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.MethodsWe 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.ResultsWe 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.ConclusionsHeterozygous 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.).

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