TREM2 Variants in Alzheimer's Disease

被引：2152

作者：

Guerreiro, Rita ^{[1
,2
]}

Wojtas, Aleksandra ^{[3
]}

Bras, Jose

Carrasquillo, Minerva ^{[3
]}

Rogaeva, Ekaterina ^{[4
]}

Majounie, Elisa ^{[3
]}

Cruchaga, Carlos ^{[5
]}

Sassi, Celeste ^{[1
,2
]}

Kauwe, John S. K. ^{[6
]}

Lupton, Michelle K. ^{[12
]}

Ryten, Mina ^{[1
]}

Brown, Kristelle ^{[15
]}

Lowe, James ^{[15
]}

Ridge, Perry G. ^{[6
,16
]}

Hammer, Monia B. ^{[2
]}

Wakutani, Yosuke ^{[4
]}

Proitsi, Petroula ^{[12
]}

Newhouse, Stephen ^{[12
]}

Lohmann, Ebba ^{[17
]}

Erginel-Unaltuna, Nihan ^{[18
]}

Medway, Christopher ^{[15
]}

Hanagasi, Hasmet ^{[17
]}

Troakes, Claire ^{[12
]}

Gurvit, Hakan ^{[17
]}

Bilgic, Basar ^{[17
]}

Al-Sarraj, Safa ^{[12
,19
]}

Benitez, Bruno ^{[5
]}

Cooper, Breanna ^{[5
]}

Carrell, David ^{[5
]}

Emre, Murat ^{[17
]}

Zou, Fanggeng ^{[3
]}

Ma, Li ^{[3
]}

Murray, Melissa E. ^{[3
]}

Dickson, Dennis W. ^{[3
]}

Younkin, Steven ^{[3
]}

Hazrati, Lilinaz ^{[4
]}

Petersen, Ronald C. ^{[20
]}

Corcoran, Christopher D. ^{[21
]}

Cai, Yefei ^{[5
]}

Oliveira, Catarina ^{[22
]}

Ribeiro, Maria Helena ^{[22
]}

Santana, Isabel ^{[22
]}

Tschanz, JoAnn T. ^{[21
]}

Gibbs, J. Raphael ^{[1
,2
]}

Norton, Maria C. ^{[21
]}

Kloszewska, Iwona ^{[23
]}

Mecocci, Patrizia ^{[24
]}

Soininen, Hilkka ^{[25
,26
]}

Tsolaki, Magda ^{[27
]}

Vellas, Bruno ^{[28
]}

机构：

[1] UCL, Inst Neurol, London WC1E 6BT, England

[2] NIA, NIH, Bethesda, MD 20892 USA

[3] Mayo Clin, Jacksonville, FL 32224 USA

[4] Univ Toronto, Tanz Ctr, Toronto, ON, Canada

[5] Washington Univ, Sch Med, St Louis, MO 63130 USA

[6] Brigham Young Univ, Provo, UT 84602 USA

[7] MRC Prion Unit, London, England

[8] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales

[9] CHRU Lille, Inst Pasteur Lille, INSERM, U744, Lille, France

[10] Univ Lille Nord France, Lille, France

[11] Univ Nottingham, Sch Mol Med Sci, Nottingham NG7 2RD, England

[12] Kings Coll London, Inst Psychiat, London, England

[13] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England

[14] UCL Inst Neurol, Reta Lila Weston Res Labs, London WC1N 3BG, England

[15] Univ Nottingham, Nottingham NG7 2RD, England

[16] ARUP Inst, Salt Lake City, UT USA

[17] Istanbul Univ, Fac Med, Istanbul, Turkey

[18] Istanbul Univ, Expt Med Res Inst, Istanbul, Turkey

[19] Kings Coll Hosp London, London, England

[20] Mayo Clin, Rochester, MN USA

[21] Utah State Univ, Logan, UT 84322 USA

[22] Univ Coimbra, Coimbra, Portugal

[23] Med Univ Lodz, Lodz, Poland

[24] Univ Perugia, I-06100 Perugia, Italy

[25] Univ Eastern Finland, Kuopio, Finland

[26] Kuopio Univ Hosp, SF-70210 Kuopio, Finland

[27] Aristotle Univ Thessaloniki, GR-54006 Thessaloniki, Greece

[28] Hop Toulouse, INSERM, UMR 1027, Toulouse, France

[29] Univ Manchester, Manchester, Lancs, England

[30] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales

来源：

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

基金：

英国惠康基金; 英国医学研究理事会; 美国国家卫生研究院; 加拿大健康研究院;

关键词：

GENOME-WIDE ASSOCIATION; IDENTIFIES VARIANTS; MISSENSE MUTATIONS; COMMON VARIANTS; GENE; MICROGLIA; FRAMEWORK; CD2AP; EPHA1; CD33;

D O I：

10.1056/NEJMoa1211851

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.)

引用

页码：117 / 127

页数：11

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