PMID- 23150908
OWN - NLM
STAT- MEDLINE
DCOM- 20130117
LR  - 20230227
IS  - 1533-4406 (Electronic)
IS  - 0028-4793 (Print)
IS  - 0028-4793 (Linking)
VI  - 368
IP  - 2
DP  - 2013 Jan 10
TI  - Variant of TREM2 associated with the risk of Alzheimer's disease.
PG  - 107-16
LID - 10.1056/NEJMoa1211103 [doi]
AB  - BACKGROUND: Sequence variants, including the epsilon4 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=3.42x10(-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=2.1x10(-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.).
FAU - Jonsson, Thorlakur
AU  - Jonsson T
AD  - deCODE Genetics, Reykjavik, Iceland.
FAU - Stefansson, Hreinn
AU  - Stefansson H
FAU - Steinberg, Stacy
AU  - Steinberg S
FAU - Jonsdottir, Ingileif
AU  - Jonsdottir I
FAU - Jonsson, Palmi V
AU  - Jonsson PV
FAU - Snaedal, Jon
AU  - Snaedal J
FAU - Bjornsson, Sigurbjorn
AU  - Bjornsson S
FAU - Huttenlocher, Johanna
AU  - Huttenlocher J
FAU - Levey, Allan I
AU  - Levey AI
FAU - Lah, James J
AU  - Lah JJ
FAU - Rujescu, Dan
AU  - Rujescu D
FAU - Hampel, Harald
AU  - Hampel H
FAU - Giegling, Ina
AU  - Giegling I
FAU - Andreassen, Ole A
AU  - Andreassen OA
FAU - Engedal, Knut
AU  - Engedal K
FAU - Ulstein, Ingun
AU  - Ulstein I
FAU - Djurovic, Srdjan
AU  - Djurovic S
FAU - Ibrahim-Verbaas, Carla
AU  - Ibrahim-Verbaas C
FAU - Hofman, Albert
AU  - Hofman A
FAU - Ikram, M Arfan
AU  - Ikram MA
FAU - van Duijn, Cornelia M
AU  - van Duijn CM
FAU - Thorsteinsdottir, Unnur
AU  - Thorsteinsdottir U
FAU - Kong, Augustine
AU  - Kong A
FAU - Stefansson, Kari
AU  - Stefansson K
LA  - eng
GR  - U01HG004438/HG/NHGRI NIH HHS/United States
GR  - U24 AG021886/AG/NIA NIH HHS/United States
GR  - U01HG004610/HG/NHGRI NIH HHS/United States
GR  - U01 HG004603/HG/NHGRI NIH HHS/United States
GR  - U01AG006781/AG/NIA NIH HHS/United States
GR  - P50-AG025688/AG/NIA NIH HHS/United States
GR  - P50 AG025688/AG/NIA NIH HHS/United States
GR  - U01 AG006781/AG/NIA NIH HHS/United States
GR  - U01HG004603/HG/NHGRI NIH HHS/United States
GR  - U01 HG004610/HG/NHGRI NIH HHS/United States
GR  - U01 HG006375/HG/NHGRI NIH HHS/United States
GR  - U01 HG004438/HG/NHGRI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20121114
PL  - United States
TA  - N Engl J Med
JT  - The New England journal of medicine
JID - 0255562
RN  - 0 (Apolipoprotein E4)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (TREM2 protein, human)
SB  - IM
CIN - N Engl J Med. 2013 Jan 10;368(2):182-4. PMID: 23151315
CIN - Nat Rev Neurol. 2013 Jan;9(1):5. PMID: 23208114
CIN - Clin Genet. 2013 Jun;83(6):525-6. PMID: 23347262
CIN - N Engl J Med. 2013 Oct 17;369(16):1568-9. PMID: 24131183
CIN - N Engl J Med. 2013 Oct 17;369(16):1564-5. PMID: 24131184
CIN - N Engl J Med. 2013 Oct 17;369(16):1565. PMID: 24131185
CIN - N Engl J Med. 2013 Oct 17;369(16):1568. PMID: 24131188
MH  - Aged, 80 and over
MH  - Alzheimer Disease/*genetics
MH  - Apolipoprotein E4/genetics
MH  - Case-Control Studies
MH  - Cognition
MH  - Genetic Variation
MH  - Genotyping Techniques
MH  - Heterozygote
MH  - Humans
MH  - Iceland
MH  - Membrane Glycoproteins/*genetics
MH  - *Mutation, Missense
MH  - Polymorphism, Single Nucleotide
MH  - Receptors, Immunologic/*genetics
MH  - Risk Factors
MH  - Sequence Analysis, DNA
PMC - PMC3677583
MID - NIHMS448531
EDAT- 2012/11/16 06:00
MHDA- 2013/01/18 06:00
PMCR- 2013/07/10
CRDT- 2012/11/16 06:00
PHST- 2012/11/16 06:00 [entrez]
PHST- 2012/11/16 06:00 [pubmed]
PHST- 2013/01/18 06:00 [medline]
PHST- 2013/07/10 00:00 [pmc-release]
AID - 10.1056/NEJMoa1211103 [doi]
PST - ppublish
SO  - N Engl J Med. 2013 Jan 10;368(2):107-16. doi: 10.1056/NEJMoa1211103. Epub 2012 
      Nov 14.