Missense variant in TREML2 protects against Alzheimer's disease.
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.
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Bruno A
BA
Benitez
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Sheng Chih
SC
Jin
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Rita
R
Guerreiro
Diagnostic Discovery Department, Genentech Inc, South San Francisco, CA, USA.
Rob
R
Graham
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Jenny
J
Lord
Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Denise
D
Harold
Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Rebecca
R
Sims
Inserm, Lille, France; Universite Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France.
Jean-Charles
JC
Lambert
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
J Raphael
JR
Gibbs
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Jose
J
Bras
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Celeste
C
Sassi
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Oscar
O
Harari
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Sarah
S
Bertelsen
Institute of Psychiatry, King's College London, London, UK.
Michelle K
MK
Lupton
Institute of Psychiatry, King's College London, London, UK.
John
J
Powell
Inserm, Lille, France; Universite Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France.
Celine
C
Bellenguez
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Kristelle
K
Brown
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Christopher
C
Medway
Diagnostic Discovery Department, Genentech Inc, South San Francisco, CA, USA.
Patrick C G
PC
Haddick
Diagnostic Discovery Department, Genentech Inc, South San Francisco, CA, USA.
Marcel P
MP
van der Brug
Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, CA, USA.
Tushar
T
Bhangale
Human Genetics Department, Genentech Inc, South San Francisco, CA, USA.
Ward
W
Ortmann
Human Genetics Department, Genentech Inc, South San Francisco, CA, USA.
Tim
T
Behrens
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.
Richard
R
Mayeux
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.
Margaret A
MA
Pericak-Vance
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.
Lindsay A
LA
Farrer
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Gerard D
GD
Schellenberg
Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.
Jonathan L
JL
Haines
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Jim
J
Turton
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Anne
A
Braae
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Imelda
I
Barber
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.
Anne M
AM
Fagan
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.
David M
DM
Holtzman
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.
John C
JC
Morris
Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Julie
J
Williams
Department of Biology, Brigham Young University, Provo, UT, USA.
John S K
JS
Kauwe
Inserm, Lille, France; Universite Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France.
Philippe
P
Amouyel
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Kevin
K
Morgan
Human Genetics Department, Genentech Inc, South San Francisco, CA, USA.
Andy
A
Singleton
Human Genetics Department, Genentech Inc, South San Francisco, CA, USA.
John
J
Hardy
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.
Alison M
AM
Goate
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.
Carlos
C
Cruchaga
D000544:Alzheimer Disease / Q000235:genetics* / Q000517:prevention & control; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002896:Chromosomes, Human, Pair 6; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D015201:Meta-Analysis as Topic; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics* / Q000502:physiology; D012306:Risk
D015415:Biomarkers; D011971:Receptors, Immunologic; C473367:TREML2 protein, human
Alzheimer's disease; Association; Conditional analysis; Endophenotype; Gene; Genome-wide association studies; TREM2