Missense variant in TREML2 protects against Alzheimer's disease

NEUROBIOLOGY OF AGING

卷:35

Article

Benitez, Bruno A.¹  Jin, Sheng Chih¹  Guerreiro, Rita^12,13  Graham, Rob⁹  Lord, Jenny³³  Harold, Denise⁸  Sims, Rebecca⁸  Lambert, Jean-Charles^35,36,37  Gibbs, J. Raphael¹³  Sassi, Celeste^12,13  Harari, Oscar¹  Bertelsen, Sarah¹  Lupton, Michelle K.³⁴  Powell, John³⁴  Bellenguez, Celine^35,36,37  Brown, Kristelle³³  Medway, Christopher³³  van der Brug, Marcel P.⁹  Bhangale, Tushar¹⁰  Ortmann, Ward¹¹  Behrens, Tim¹¹  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  Braae, Anne³³  Barber, Imelda³³  Fagan, Anne M.^2,6,7  Holtzman, David M.^2,5,6,7  Morris, John C.^2,3,5,6,7  Kauwe, John S. K.¹⁴  Amouyel, Philippe^35,36,37  Morgan, Kevin³³  Singleton, Andy¹¹  Hardy, John¹¹  Goate, Alison M.^1,2,4,6,7  Cruchaga, Carlos^1,7,36 

[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

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

DOI  :  10.1016/j.neurobiolaging.2013.12.010

来源: Elsevier

【 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.

【 授权许可】

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