Missense variant in TREML2 protects against Alzheimer's disease

被引：98

作者：

Benitez, Bruno A. ^{[1
]}

Jin, Sheng Chih ^{[1
]}

Guerreiro, Rita ^{[12
,13
]}

Graham, Rob ^{[9
]}

Lord, Jenny ^{[33
]}

Harold, Denise ^{[8
]}

Sims, Rebecca ^{[8
]}

Lambert, Jean-Charles ^{[35
,36
,37
]}

Gibbs, J. Raphael ^{[13
]}

Bras, Jose

Sassi, Celeste ^{[12
,13
]}

Harari, Oscar ^{[1
]}

Bertelsen, Sarah ^{[1
]}

Lupton, Michelle K. ^{[34
]}

Powell, John ^{[34
]}

Bellenguez, Celine ^{[35
,36
,37
]}

Brown, Kristelle ^{[33
]}

Medway, Christopher ^{[33
]}

Haddick, Patrick C. G.

van der Brug, Marcel P. ^{[9
]}

Bhangale, Tushar ^{[10
]}

Ortmann, Ward ^{[11
]}

Behrens, Tim ^{[11
]}

Mayeux, Richard ^{[15
,16
]}

Pericak-Vance, Margaret A. ^{[17
,18
]}

Farrer, Lindsay A. ^{[19
,20
,21
,22
,23
,24
,25
,26
,27
,28
,29
,30
]}

Schellenberg, Gerard D. ^{[31
]}

Haines, Jonathan L. ^{[32
]}

Turton, Jim

Braae, Anne ^{[33
]}

Barber, Imelda ^{[33
]}

Fagan, Anne M. ^{[2
,6
,7
]}

Holtzman, David M. ^{[2
,5
,6
,7
]}

Morris, John C. ^{[2
,3
,5
,6
,7
]}

Williams, Julie

Kauwe, John S. K. ^{[14
]}

Amouyel, Philippe ^{[35
,36
,37
]}

Morgan, Kevin ^{[33
]}

Singleton, Andy ^{[11
]}

Hardy, John ^{[11
]}

Goate, Alison M. ^{[1
,2
,4
,6
,7
]}

Cruchaga, Carlos ^{[1
,7
,36
]}

机构：

[1] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[5] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA

[6] Washington Univ, Sch Med, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA

[7] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA

[8] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales

[9] Genentech Inc, Diagnost Discovery Dept, San Francisco, CA 94080 USA

[10] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA 94080 USA

[11] Genentech Inc, Dept Human Genet, San Francisco, CA 94080 USA

[12] UCL Inst Neurol, Dept Mol Neurosci, London, England

[13] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA

[14] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA

[15] Columbia Univ, Taub Inst Alzheimers Dis & Aging Brain, Dept Neurol, New York, NY USA

[16] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA

[17] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA

[18] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL USA

[19] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA

[20] Boston Univ, Sch Publ Hlth, Dept Med, Boston, MA USA

[21] Boston Univ, Sch Med, Dept Biomed Genet, Boston, MA 02118 USA

[22] Boston Univ, Sch Publ Hlth, Dept Biomed Genet, Boston, MA USA

[23] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[24] Boston Univ, Sch Publ Hlth, Dept Neurol, Boston, MA USA

[25] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA

[26] Boston Univ, Sch Publ Hlth, Dept Ophthalmol, Boston, MA USA

[27] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA

[28] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[29] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA

[30] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[31] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[32] Vanderbilt Univ, Vanderbilt Ctr Human Genet Res, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA

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

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

[35] INSERM, F-59045 Lille, France

[36] Univ Lille 2, Lille, France

[37] Inst Pasteur, F-59019 Lille, France

来源：

NEUROBIOLOGY OF AGING | 2014年 / 35卷 / 06期

关键词：

TREM2; Genome-wide association studies; Conditional analysis; Endophenotype; Gene; Alzheimer's disease; Association;

D O I：

10.1016/j.neurobiolaging.2013.12.010

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p. R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p. R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p. S144G (rs3747742) as a potential driver of the metaanalysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD. (C) 2014 Elsevier Inc. All rights reserved.

引用

页码：1510.e19 / 1510.e26

页数：8

共 25 条

[1] Vascular factors and risk of dementia: Design of the three-city study and baseline characteristics of the study population [J].

Alperovitch, A .

NEUROEPIDEMIOLOGY, 2003, 22 (06) :316-325

[2] TREM2 and Neurodegenerative Disease REPLY [J].

Jonsson, Thorlakur ;

Stefansson, Kari .

NEW ENGLAND JOURNAL OF MEDICINE, 2013, 369 (16) :1568-1569

[3] TREM2 is associated with the risk of Alzheimer's disease in Spanish population [J].

Benitez, Bruno A. ;

Cooper, Breanna ;

Pastor, Pau ;

Jin, Sheng-Chih ;

Lorenzo, Elena ;

Cervantes, Sebastian ;

Cruchaga, Carlos .

NEUROBIOLOGY OF AGING, 2013, 34 (06) :1711.e15-1711.e17

[4] Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis [J].

Benitez, Bruno A. ;

Alvarado, David ;

Cai, Yefei ;

Mayo, Kevin ;

Chakraverty, Sumitra ;

Norton, Joanne ;

Morris, John C. ;

Sands, Mark S. ;

Goate, Alison ;

Cruchaga, Carlos .

PLOS ONE, 2011, 6 (11)

[5] TREM2 and Neurodegenerative Disease REPLY [J].

Jonsson, Thorlakur ;

Stefansson, Kari .

NEW ENGLAND JOURNAL OF MEDICINE, 2013, 369 (16) :1568-1569

[6]

Cruchaga C., 2013, NEURON

[7] Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimers disease [J].

Cruchaga, Carlos ;

Kauwe, John S. K. ;

Nowotny, Petra ;

Bales, Kelly ;

Pickering, Eve H. ;

Mayo, Kevin ;

Bertelsen, Sarah ;

Hinrichs, Anthony ;

Fagan, Anne M. ;

Holtzman, David M. ;

Morris, John C. ;

Goate, Alison M. .

HUMAN MOLECULAR GENETICS, 2012, 21 (20) :4558-4571

[8] ssociation and Expression Analyses With Single-Nucleotide Polymorphisms in TOMM40 in Alzheimer Disease [J].

Cruchaga, Carlos ;

Nowotny, Petra ;

Kauwe, John S. K. ;

Ridge, Perry G. ;

Mayo, Kevin ;

Bertelsen, Sarah ;

Hinrichs, Anthony ;

Fagan, Anne M. ;

Holtzman, David M. ;

Morris, John C. ;

Goate, Alison M. .

ARCHIVES OF NEUROLOGY, 2011, 68 (08) :1013-1019

[9] SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease [J].

Cruchaga, Carlos ;

Kauwe, John S. K. ;

Mayo, Kevin ;

Spiegel, Noah ;

Bertelsen, Sarah ;

Nowotny, Petra ;

Shah, Aarti R. ;

Abraham, Richard ;

Hollingworth, Paul ;

Harold, Denise ;

Owen, Michael M. ;

Williams, Julie ;

Lovestone, Simon ;

Peskind, Elaine R. ;

Li, Ge ;

Leverenz, James B. ;

Galasko, Douglas ;

Morris, John C. ;

Fagan, Anne M. ;

Holtzman, David M. ;

Goate, Alison M. .

PLOS GENETICS, 2010, 6 (09)

[10] Cortical Atrophy and Language Network Reorganization Associated with a Novel Progranulin Mutation [J].

Cruchaga, Carlos ;

Fernandez-Seara, Maria A. ;

Seijo-Martinez, Manuel ;

Samaranch, Lluis ;

Lorenzo, Elena ;

Hinrichs, Anthony ;

Irigoyen, Jaione ;

Maestro, Cristina ;

Prieto, Elena ;

Marti-Climent, Josep M. ;

Arbizu, Javier ;

Pastor, Maria A. ;

Pastor, Pau .

CEREBRAL CORTEX, 2009, 19 (08) :1751-1760

← 1 2 3 →