title: TREM2 variants in Alzheimer's disease.
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.).
authors.affiliation: University College London (UCL) Institute of Neurology, London, United Kingdom.
authors.forename: Rita
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authors.forename: Aleksandra
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authors.lastname: Wojtas
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authors.forename: Minerva
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authors.forename: Ekaterina
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authors.lastname: Rogaeva
authors.forename: Elisa
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authors.lastname: Majounie
authors.forename: Carlos
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authors.lastname: Cruchaga
authors.forename: Celeste
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authors.lastname: Sassi
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
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authors.lastname: Younkin
authors.forename: Lilinaz
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authors.lastname: Hazrati
authors.forename: John
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authors.lastname: Collinge
authors.forename: Jennifer
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authors.lastname: Pocock
authors.forename: Tammaryn
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authors.lastname: Lashley
authors.forename: Julie
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authors.lastname: Williams
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.forename: Philippe
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authors.lastname: Amouyel
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: John
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authors.lastname: Hardy
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology; D059472:Exome / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D060005:Genotyping Techniques; D006579:Heterozygote; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C498715:TREM2 protein, human