Year: 2012
Type: article
Study design: Observational Study
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<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.).
Source: New England Journal of Medicine
Authors: 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
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Health and Human Services, University of Dundee, Wellcome Trust, Alzheimer Society, National Institute for Health and Care Research, University College London, Fondation pour la Recherche sur Alzheimer, National Institutes of Health, Canadian Institutes of Health Research, Medical Research Council, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: G1347952586, NIHR Senior Investigator Award, Pleiotropic and Interaction Effects on Alzheimer's disease Risk and Progression, G2845388095, Plasma AB as a Surrogate Genetic Marker for LOAD, A systematic investigation into the pathogenesis and course of Parkinson's syndrome, Further defining the genetic architecture of Alzheimer's disease, Alzheimers Disease Patient Registry, G4011959119, Mechanisms of neurotoxicity of amyloid aggregates., Epidemiology of Familial Late-Onset Alzheimer's Disease, Alzheimer's Disease Research Center - Overall, Genetic Analysis Of Alzheimer s Disease, Alzheimer's Disease Research Center, Understanding the mechanics of presenilin-dependent regulated intra-membranous proteolysis., Translational Neuroscientist and the Hope Center, A systematic investigation into the pathogenesis and course of Parkinson's syndrome., Autophagy in health and disease., National Institute on Aging Alzheimer's Disease Family-Based Study (NIA-AD FBS), National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), Mayo Alzheimer's Disease Research Center
OpenAlex ID: W2124490243