Variant of TREM2 Associated with the Risk of Alzheimer's Disease

被引：1851

作者：

Jonsson, Thorlakur ^{[1
]}

Stefansson, Hreinn ^{[1
]}

Steinberg, Stacy ^{[1
]}

Jonsdottir, Ingileif ^{[1
,2
]}

Jonsson, Palmi V. ^{[2
,3
]}

Snaedal, Jon ^{[3
]}

Bjornsson, Sigurbjorn ^{[3
]}

Huttenlocher, Johanna ^{[4
]}

Levey, Allan I. ^{[7
]}

Lah, James J. ^{[7
]}

Rujescu, Dan ^{[5
]}

Hampel, Harald ^{[6
]}

Giegling, Ina ^{[5
]}

Andreassen, Ole A. ^{[8
,10
]}

Engedal, Knut ^{[9
,10
]}

Ulstein, Ingun ^{[9
]}

Djurovic, Srdjan ^{[8
,10
]}

Ibrahim-Verbaas, Carla ^{[11
]}

Hofman, Albert ^{[11
]}

Ikram, M. Arfan ^{[11
]}

van Duijn, Cornelia M. ^{[11
]}

Thorsteinsdottir, Unnur ^{[1
,2
]}

Kong, Augustine ^{[1
]}

Stefansson, Kari ^{[1
,2
]}

机构：

[1] DeCODE Genet, IS-101 Reykjavik, Iceland

[2] Univ Iceland, Fac Med, Reykjavik, Iceland

[3] Landspitali Univ Hosp, Reykjavik, Iceland

[4] Inst Human Genet, Dept Med Genet, Tubingen, Germany

[5] Univ Halle Wittenberg, D-06108 Halle, Germany

[6] Univ Frankfurt Main, Dept Psychiat, Frankfurt, Germany

[7] Emory Univ, Sch Med, Dept Neurol, Alzheimers Dis Ctr, Atlanta, GA 30322 USA

[8] Univ Oslo, Oslo Univ Hosp, KG Jebsen Ctr Psychosis Res, Div Mental Hlth & Addict, Oslo, Norway

[9] Univ Oslo, Oslo Univ Hosp, Norwegian Ctr Aging & Hlth, Dept Geriatr, Oslo, Norway

[10] Univ Oslo, Inst Clin Med, Oslo, Norway

[11] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2013年 / 368卷 / 02期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; APOLIPOPROTEIN-E; CUTTING EDGE; MUTATIONS; RESPONSES; INFLAMMATION; EXPRESSION; FREQUENCY; DEMENTIA; SYSTEM;

D O I：

10.1056/NEJMoa1211103

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Sequence variants, including the epsilon 4 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.)

引用

页码：107 / 116

页数：10

共 51 条

[11] Mutations in TREM2 Lead to Pure Early-Onset Dementia Without Bone Cysts [J].