The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease.
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.
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.
Christina M
CM
Lill
Department of Neurology, Oslo University Hospital, Oslo, Norway.
Aina
A
Rengmark
Department of Neurology, Oslo University Hospital, Oslo, Norway.
Lasse
L
Pihlstrøm
Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, UK.
Isabella
I
Fogh
Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, UK.
Aleksey
A
Shatunov
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.
Patrick M
PM
Sleiman
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Li-San
LS
Wang
Max Planck Institute for Human Development, Berlin, Germany.
Tian
T
Liu
Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
Christina F
CF
Lassen
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Esther
E
Meissner
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
Panos
P
Alexopoulos
Rita Levi Montalcini Department of Neuroscience, ALS Center, University of Torino, Torino, Italy.
Andrea
A
Calvo
Rita Levi Montalcini Department of Neuroscience, ALS Center, University of Torino, Torino, Italy; Neuroscience Institute of Turin, Turin, Italy.
Adriano
A
Chio
Department of Neurology, Linköping University, Linköping, Sweden.
Nil
N
Dizdar
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University of Frankfurt, Frankfurt, Germany.
Frank
F
Faltraco
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Lars
L
Forsgren
Department of Neurology, University of Ulm, Ulm, Germany.
Julia
J
Kirchheiner
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
Alexander
A
Kurz
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
Jan P
JP
Larsen
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Maria
M
Liebsch
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Jan
J
Linder
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.
Karen E
KE
Morrison
Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Hans
H
Nissbrandt
Department of Neurology, University of Ulm, Ulm, Germany.
Markus
M
Otto
Department of Neuro-/Pathology, University of Oslo and Oslo University Hospital, Oslo, Norway; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
Jens
J
Pahnke
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Amanda
A
Partch
Department of Clinical Pathology, Molecular Genetics Unit, Azienda Ospedaliera Città della Salute e della Scienza, Torino, Italy.
Gabriella
G
Restagno
Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
Dan
D
Rujescu
Department of Neurology, University of Ulm, Ulm, Germany.
Cathrin
C
Schnack
Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, UK.
Christopher E
CE
Shaw
Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, UK.
Pamela J
PJ
Shaw
Department of Neurology, University of Ulm, Ulm, Germany.
Hayrettin
H
Tumani
Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Ole-Bjørn
OB
Tysnes
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Otto
O
Valladares
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.
Vincenzo
V
Silani
Department of Neurology, Neuromuscular Diseases Brain Center Rudolf Magnus, Netherlands ALS Center, University Medical Center Utrecht, Utrecht, The Netherlands.
Leonard H
LH
van den Berg
Department of Neurology, Neuromuscular Diseases Brain Center Rudolf Magnus, Netherlands ALS Center, University Medical Center Utrecht, Utrecht, The Netherlands.
Wouter
W
van Rheenen
Department of Neurology, Neuromuscular Diseases Brain Center Rudolf Magnus, Netherlands ALS Center, University Medical Center Utrecht, Utrecht, The Netherlands.
Jan H
JH
Veldink
Max Planck Institute for Human Development, Berlin, Germany.
Ulman
U
Lindenberger
Interdisciplinary Metabolic Center, Lipids Clinic, Charité University Medicine, Berlin, Germany.
Elisabeth
E
Steinhagen-Thiessen
German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany; Department of Psychosomatic Medicine, University of Rostock, Rostock, Germany.
Stefan
S
Teipel
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.
Robert
R
Perneczky
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.
Hakon
H
Hakonarson
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.
Harald
H
Hampel
Department of Neurology, University of Ulm, Ulm, Germany.
Christine A F
CAF
von Arnim
Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
Jørgen H
JH
Olsen
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Vivianna M
VM
Van Deerlin
Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, UK.
Ammar
A
Al-Chalabi
Department of Neurology, Oslo University Hospital, Oslo, Norway.
Mathias
M
Toft
Department of Epidemiology and Environmental Sciences, School of Public Health, University of California, Los Angeles, CA, USA.
Beate
B
Ritz
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.
Lars
L
Bertram
D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics; D040641:Quantitative Trait Loci; D011971:Receptors, Immunologic / Q000235:genetics*; D012307:Risk Factors; D044465:White People; D016875:tau Proteins / Q000134:cerebrospinal fluid
D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; D016875:tau Proteins
Alzheimer disease; Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; GWAS; Genetic association; Imputation; Meta-analysis; Neurodegenerative disease; Parkinson disease; R47H; Rare variant; TREM2; rs75932628