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 C G 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; 3C Study Group; EADI consortium; Alzheimer's Disease Genetic Consortium (ADGC); Alzheimer's Disease Neuroimaging Initiative (ADNI); GERAD Consortium; 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

Missense variant in TREML2 protects against Alzheimer's disease

Neurobiol Aging. 2014 Jun;35(6):1510.e19-26. doi: 10.1016/j.neurobiolaging.2013.12.010. Epub 2013 Dec 21.

Authors

Bruno A Benitez¹, Sheng Chih Jin¹, Rita Guerreiro², Rob Graham³, Jenny Lord⁴, Denise Harold⁵, Rebecca Sims⁵, Jean-Charles Lambert⁶, J Raphael Gibbs², Jose Bras⁷, Celeste Sassi², Oscar Harari¹, Sarah Bertelsen¹, Michelle K Lupton⁸, John Powell⁸, Celine Bellenguez⁶, Kristelle Brown⁴, Christopher Medway⁴, Patrick C G Haddick³, Marcel P van der Brug³, Tushar Bhangale⁹, Ward Ortmann¹⁰, Tim Behrens¹⁰, Richard Mayeux¹¹, Margaret A Pericak-Vance¹², Lindsay A Farrer¹³, Gerard D Schellenberg¹⁴, Jonathan L Haines¹⁵, Jim Turton⁴, Anne Braae⁴, Imelda Barber⁴, Anne M Fagan¹⁶, David M Holtzman¹⁷, John C Morris¹⁸; 3C Study Group; EADI consortium; Alzheimer's Disease Genetic Consortium (ADGC); Alzheimer's Disease Neuroimaging Initiative (ADNI); GERAD Consortium; Julie Williams⁵, John S K Kauwe¹⁹, Philippe Amouyel⁶, Kevin Morgan⁴, Andy Singleton¹⁰, John Hardy¹⁰, Alison M Goate²⁰, Carlos Cruchaga²¹

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
² Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³ Diagnostic Discovery Department, Genentech Inc, South San Francisco, CA, USA.
⁴ Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
⁵ Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
⁶ Inserm, Lille, France; Universite Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France.
⁷ Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
⁸ Institute of Psychiatry, King's College London, London, UK.
⁹ Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, CA, USA.
¹⁰ Human Genetics Department, Genentech Inc, South San Francisco, CA, USA.
¹¹ Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA.
¹² The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA; Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.
¹³ Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Biomedical Genetics, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
¹⁴ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.
¹⁶ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
¹⁷ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
¹⁸ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
¹⁹ Department of Biology, Brigham Young University, Provo, UT, USA.
²⁰ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: goatea@psychiatry.wustl.edu.
²¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA; Universite Lille 2, Lille, France. Electronic address: cruchagac@psychiatry.wustl.edu.

PMID: 24439484
PMCID: PMC3961557
DOI: 10.1016/j.neurobiolaging.2013.12.010

Abstract

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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics*
Alzheimer Disease / prevention & control
Biomarkers / cerebrospinal fluid
Chromosomes, Human, Pair 6
Genetic Variation / genetics*
Genome-Wide Association Study*
Humans
Meta-Analysis as Topic
Mutation, Missense / genetics*
Polymorphism, Single Nucleotide / genetics
Receptors, Immunologic / genetics*
Receptors, Immunologic / physiology
Risk

Substances

Biomarkers
Receptors, Immunologic
TREML2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding