Missense variant in TREML2 protects against Alzheimer's disease

Bruno A Benitez; Sheng Chih Jin; Rita Guerreiro; Rob Graham; Jenny Lord; Denise Harold; Rebecca Sims; Jean-Charles Lambert; J. Raphael Gibbs; Jose Bras; Celeste Sassi; Oscar Harari; Sarah Bertelsen; Michelle K Lupton; John Powell; Celine Bellenguez; Kristelle Brown; Christopher Medway; Patrick CG Haddick; Marcel P van der Brug; Tushar Bhangale; Ward Ortmann; Tim Behrens; Richard Mayeux; Margaret A Pericak-Vance; Lindsay A Farrer; Gerard D Schellenberg; Jonathan L Haines; Jim Turton; Anne Braae; Imelda Barber; Anne M Fagan; David M Holtzman; John C Morris; Julie Williams; John S.K Kauwe; Philippe Amouyel; Kevin Morgan; Andy Singleton; John Hardy; Alison M Goate; Carlos Cruchaga

doi:10.1016/j.neurobiolaging.2013.12.010

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Missense variant in TREML2 protects against Alzheimer's disease

Journal article

Open access

Peer reviewed

Missense variant in TREML2 protects against Alzheimer's disease

Bruno A Benitez, Sheng Chih Jin, Rita Guerreiro, Rob Graham, Jenny Lord, Denise Harold, Rebecca Sims, Jean-Charles Lambert, J. Raphael Gibbs, Jose Bras, …

Neurobiology of aging, Vol.35(6), pp.1510.e19-1510.e26

2014-06

DOI: https://doi.org/10.1016/j.neurobiolaging.2013.12.010

PMCID: PMC3961557

PMID: 24439484

Abstract

Genome-wide association studies

Association

Gene

Conditional analysis

TREM2

Alzheimer's disease

Endophenotype

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 meta-analysis 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.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.57 Alzheimer's Disease
Web Of Science research areas: Geriatrics & Gerontology; Neurosciences
ESI research areas: Neuroscience & Behavior

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Title: Missense variant in TREML2 protects against Alzheimer's disease
Creators: Bruno A Benitez - Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
Sheng Chih Jin - Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
Rita Guerreiro - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Rob Graham - Diagnostic Discovery Department, Genentech Inc, South San Francisco, CA, USA
Jenny Lord - Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK
Denise Harold - Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
Rebecca Sims - Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
Jean-Charles Lambert - Inserm, Lille, France
J. Raphael Gibbs - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Jose Bras - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Celeste Sassi - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Oscar Harari - Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
Sarah Bertelsen - Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
Michelle K Lupton - Institute of Psychiatry, King's College London, London, UK
John Powell - Institute of Psychiatry, King's College London, London, UK
Celine Bellenguez - Inserm, Lille, France
Kristelle Brown - Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK
Christopher Medway - Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK
Patrick CG Haddick - Diagnostic Discovery Department, Genentech Inc, South San Francisco, CA, USA
Marcel P van der Brug - Diagnostic Discovery Department, Genentech Inc, South San Francisco, CA, USA
Tushar Bhangale - Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, CA, USA
Ward Ortmann - Human Genetics Department, Genentech Inc, South San Francisco, CA, USA
Tim Behrens - Human Genetics Department, Genentech Inc, South San Francisco, CA, USA
Richard Mayeux - Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA
Margaret A Pericak-Vance - The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA
Lindsay A Farrer - Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, MA, USA
Gerard D Schellenberg - Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Jonathan L Haines - Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA
Jim Turton - Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK
Anne Braae - Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK
Imelda Barber - Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK
Anne M Fagan - Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
David M Holtzman - Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
John C Morris - Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
Julie Williams - Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
John S.K Kauwe - Department of Biology, Brigham Young University, Provo, UT, USA
Philippe Amouyel - Inserm, Lille, France
Kevin Morgan - Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK
Andy Singleton - Human Genetics Department, Genentech Inc, South San Francisco, CA, USA
John Hardy - Human Genetics Department, Genentech Inc, South San Francisco, CA, USA
Alison M Goate - Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
Carlos Cruchaga - Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
Publication Details: Neurobiology of aging, Vol.35(6), pp.1510.e19-1510.e26
Publisher: Elsevier Inc
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 24439484
PMCID: PMC3961557
Record Identifier: 991031578665302976