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

Missense variant in TREML2 protects against Alzheimer's disease.

Author information

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.

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

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