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Alzheimers Dement. 2015 Dec;11(12):1407-1416. doi: 10.1016/j.jalz.2014.12.009. Epub 2015 Apr 30.

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease.

Author information

1
Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany. Electronic address: christina.lill@gmx.de.
2
Department of Neurology, Oslo University Hospital, Oslo, Norway.
3
Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, UK.
4
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Human Genetics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
6
Max Planck Institute for Human Development, Berlin, Germany.
7
Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
8
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
9
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
10
Rita Levi Montalcini Department of Neuroscience, ALS Center, University of Torino, Torino, Italy.
11
Rita Levi Montalcini Department of Neuroscience, ALS Center, University of Torino, Torino, Italy; Neuroscience Institute of Turin, Turin, Italy.
12
Department of Neurology, Linköping University, Linköping, Sweden.
13
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University of Frankfurt, Frankfurt, Germany.
14
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
15
Department of Neurology, University of Ulm, Ulm, Germany.
16
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
17
School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Neurosciences Division, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
18
Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
19
Department of Neuro-/Pathology, University of Oslo and Oslo University Hospital, Oslo, Norway; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
20
Department of Clinical Pathology, Molecular Genetics Unit, Azienda Ospedaliera Città della Salute e della Scienza, Torino, Italy.
21
Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
22
Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, UK.
23
Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
24
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano, Italy; Department of Pathophysiology and Tranplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milano, Italy.
25
Department of Neurology, Neuromuscular Diseases Brain Center Rudolf Magnus, Netherlands ALS Center, University Medical Center Utrecht, Utrecht, The Netherlands.
26
Interdisciplinary Metabolic Center, Lipids Clinic, Charité University Medicine, Berlin, Germany.
27
German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany; Department of Psychosomatic Medicine, University of Rostock, Rostock, Germany.
28
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany; Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London, UK; West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London, UK.
29
AXA Research Fund & UPMC Chair, Paris, France; Département de Neurologie, Sorbonne Universités, Université Pierre et Marie Curie, Institut de la Mémoire et de la Maladie d'Alzheimer & Institut du Cerveau et de la Moelle épinière (ICM), Hôpital de la Pitié-Salpétrière, Paris, France.
30
Department of Epidemiology and Environmental Sciences, School of Public Health, University of California, Los Angeles, CA, USA.
31
Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany; Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London, UK.

Abstract

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.

KEYWORDS:

Alzheimer disease; Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; GWAS; Genetic association; Imputation; Meta-analysis; Neurodegenerative disease; Parkinson disease; R47H; Rare variant; TREM2; rs75932628

PMID:
25936935
PMCID:
PMC4627856
DOI:
10.1016/j.jalz.2014.12.009
[Indexed for MEDLINE]
Free PMC Article

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