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

Christina M Lill; Aina Rengmark; Lasse Pihlstrøm; Isabella Fogh; Aleksey Shatunov; Patrick M Sleiman; Li-San Wang; Tian Liu; Christina F Lassen; Esther Meissner; Panos Alexopoulos; Andrea Calvo; Adriano Chio; Nil Dizdar; Frank Faltraco; Lars Forsgren; Julia Kirchheiner; Alexander Kurz; Jan P Larsen; Maria Liebsch; Jan Linder; Karen E Morrison; Hans Nissbrandt; Markus Otto; Jens Pahnke; Amanda Partch; Gabriella Restagno; Dan Rujescu; Cathrin Schnack; Christopher E Shaw; Pamela J Shaw; Hayrettin Tumani; Ole-Bjørn Tysnes; Otto Valladares; Vincenzo Silani; Leonard H van den Berg; Wouter van Rheenen; Jan H Veldink; Ulman Lindenberger; Elisabeth Steinhagen-Thiessen; SLAGEN Consortium; Stefan Teipel; Robert Perneczky; Hakon Hakonarson; Harald Hampel; Christine A F von Arnim; Jørgen H Olsen; Vivianna M Van Deerlin; Ammar Al-Chalabi; Mathias Toft; Beate Ritz; Lars Bertram

doi:10.1016/j.jalz.2014.12.009

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

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

Authors

Christina M Lill¹, Aina Rengmark², Lasse Pihlstrøm², Isabella Fogh³, Aleksey Shatunov³, Patrick M Sleiman⁴, Li-San Wang⁵, Tian Liu⁶, Christina F Lassen⁷, Esther Meissner⁸, Panos Alexopoulos⁹, Andrea Calvo¹⁰, Adriano Chio¹¹, Nil Dizdar¹², Frank Faltraco¹³, Lars Forsgren¹⁴, Julia Kirchheiner¹⁵, Alexander Kurz⁹, Jan P Larsen¹⁶, Maria Liebsch⁸, Jan Linder¹⁴, Karen E Morrison¹⁷, Hans Nissbrandt¹⁸, Markus Otto¹⁵, Jens Pahnke¹⁹, Amanda Partch⁵, Gabriella Restagno²⁰, Dan Rujescu²¹, Cathrin Schnack¹⁵, Christopher E Shaw³, Pamela J Shaw²², Hayrettin Tumani¹⁵, Ole-Bjørn Tysnes²³, Otto Valladares⁵, Vincenzo Silani²⁴, Leonard H van den Berg²⁵, Wouter van Rheenen²⁵, Jan H Veldink²⁵, Ulman Lindenberger⁶, Elisabeth Steinhagen-Thiessen²⁶; SLAGEN Consortium; Stefan Teipel²⁷, Robert Perneczky²⁸, Hakon Hakonarson⁴, Harald Hampel²⁹, Christine A F von Arnim¹⁵, Jørgen H Olsen⁷, Vivianna M Van Deerlin⁵, Ammar Al-Chalabi³, Mathias Toft², Beate Ritz³⁰, Lars Bertram³¹

Affiliations

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: [email protected].
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.

Publication types

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

MeSH terms

Aged
Alleles
Alzheimer Disease / genetics*
Amyotrophic Lateral Sclerosis / genetics
Case-Control Studies
Female
Frontotemporal Lobar Degeneration / genetics
Genetic Predisposition to Disease*
Genotype
Humans
Male
Membrane Glycoproteins / genetics*
Middle Aged
Neurodegenerative Diseases / genetics*
Parkinson Disease / genetics
Quantitative Trait Loci
Receptors, Immunologic / genetics*
Risk Factors
White People
tau Proteins / cerebrospinal fluid

Substances

Membrane Glycoproteins
Receptors, Immunologic
TREM2 protein, human
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding