title: Variant of TREM2 associated with the risk of Alzheimer's disease.
abstract: BACKGROUND
  Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found.
  
  
  METHODS
  We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, The Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons.
  
  
  RESULTS
  A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10(-10)). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10(-12) in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003).
  
  
  CONCLUSIONS
  Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.).
authors.affiliation: deCODE Genetics, Reykjavik, Iceland.
authors.forename: Thorlakur
authors.initials: T
authors.lastname: Jonsson
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.forename: Stacy
authors.initials: S
authors.lastname: Steinberg
authors.forename: Ingileif
authors.initials: I
authors.lastname: Jonsdottir
authors.forename: Palmi V
authors.initials: PV
authors.lastname: Jonsson
authors.forename: Jon
authors.initials: J
authors.lastname: Snaedal
authors.forename: Sigurbjorn
authors.initials: S
authors.lastname: Bjornsson
authors.forename: Johanna
authors.initials: J
authors.lastname: Huttenlocher
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Harald
authors.initials: H
authors.lastname: Hampel
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.forename: Knut
authors.initials: K
authors.lastname: Engedal
authors.forename: Ingun
authors.initials: I
authors.lastname: Ulstein
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.forename: Carla
authors.initials: C
authors.lastname: Ibrahim-Verbaas
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D016022:Case-Control Studies; D003071:Cognition; D014644:Genetic Variation; D060005:Genotyping Techniques; D006579:Heterozygote; D006801:Humans; D007055:Iceland; D008562:Membrane Glycoproteins / Q000235:genetics*; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: D053327:Apolipoprotein E4; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human