%0 Journal Article %J N Engl J Med %D 2013 %T TREM2 variants in Alzheimer's disease. %A Guerreiro, Rita %A Wojtas, Aleksandra %A Bras, Jose %A Carrasquillo, Minerva %A Rogaeva, Ekaterina %A Majounie, Elisa %A Cruchaga, Carlos %A Sassi, Celeste %A Kauwe, John S K %A Younkin, Steven %A Hazrati, Lilinaz %A Collinge, John %A Pocock, Jennifer %A Lashley, Tammaryn %A Williams, Julie %A Lambert, Jean-Charles %A Amouyel, Philippe %A Goate, Alison %A Rademakers, Rosa %A Morgan, Kevin %A Powell, John %A St George-Hyslop, Peter %A Singleton, Andrew %A Hardy, John %K Aged %K Alzheimer Disease %K Animals %K Brain %K Exome %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Genotyping Techniques %K Heterozygote %K Humans %K Membrane Glycoproteins %K Mice %K Mice, Inbred A %K Mutation %K Receptors, Immunologic %K Risk Factors %K RNA, Messenger %K Sequence Analysis, DNA %X

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.).

%B N Engl J Med %V 368 %P 117-27 %8 2013 Jan 10 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23150934?dopt=Abstract %R 10.1056/NEJMoa1211851 %0 Journal Article %J PLoS One %D 2010 %T Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. %A Jones, Lesley %A Holmans, Peter A %A Hamshere, Marian L %A Harold, Denise %A Moskvina, Valentina %A Ivanov, Dobril %A Pocklington, Andrew %A Abraham, Richard %A Hollingworth, Paul %A Sims, Rebecca %A Gerrish, Amy %A Pahwa, Jaspreet Singh %A Jones, Nicola %A Stretton, Alexandra %A Morgan, Angharad R %A Lovestone, Simon %A Powell, John %A Proitsi, Petroula %A Lupton, Michelle K %A Brayne, Carol %A Rubinsztein, David C %A Gill, Michael %A Lawlor, Brian %A Lynch, Aoibhinn %A Morgan, Kevin %A Brown, Kristelle S %A Passmore, Peter A %A Craig, David %A McGuinness, Bernadette %A Todd, Stephen %A Holmes, Clive %A Mann, David %A Smith, A David %A Love, Seth %A Kehoe, Patrick G %A Mead, Simon %A Fox, Nick %A Rossor, Martin %A Collinge, John %A Maier, Wolfgang %A Jessen, Frank %A Schürmann, Britta %A Heun, Reinhard %A Kölsch, Heike %A van den Bussche, Hendrik %A Heuser, Isabella %A Peters, Oliver %A Kornhuber, Johannes %A Wiltfang, Jens %A Dichgans, Martin %A Frölich, Lutz %A Hampel, Harald %A Hüll, Michael %A Rujescu, Dan %A Goate, Alison M %A Kauwe, John S K %A Cruchaga, Carlos %A Nowotny, Petra %A Morris, John C %A Mayo, Kevin %A Livingston, Gill %A Bass, Nicholas J %A Gurling, Hugh %A McQuillin, Andrew %A Gwilliam, Rhian %A Deloukas, Panos %A Al-Chalabi, Ammar %A Shaw, Christopher E %A Singleton, Andrew B %A Guerreiro, Rita %A Mühleisen, Thomas W %A Nöthen, Markus M %A Moebus, Susanne %A Jöckel, Karl-Heinz %A Klopp, Norman %A Wichmann, H-Erich %A Rüther, Eckhard %A Carrasquillo, Minerva M %A Pankratz, V Shane %A Younkin, Steven G %A Hardy, John %A O'Donovan, Michael C %A Owen, Michael J %A Williams, Julie %K Alzheimer Disease %K Apolipoproteins E %K Cholesterol %K Chromosome Mapping %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Immune System %K Polymorphism, Single Nucleotide %X

BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.

METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.

SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

%B PLoS One %V 5 %P e13950 %8 2010 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21085570?dopt=Abstract %R 10.1371/journal.pone.0013950