Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

Barbara Schormair; Chen Zhao; Steven Bell; Erik Tilch; Aaro V Salminen; Benno Pütz; Yves Dauvilliers; Ambra Stefani; Birgit Högl; Werner Poewe; David Kemlink; Karel Sonka; Cornelius G Bachmann; Walter Paulus; Claudia Trenkwalder; Wolfgang H Oertel; Magdolna Hornyak; Maris Teder-Laving; Andres Metspalu; Georgios M Hadjigeorgiou; Olli Polo; Ingo Fietze; Owen A Ross; Zbigniew Wszolek; Adam S Butterworth; Nicole Soranzo; Willem H Ouwehand; David J Roberts; John Danesh; Richard P Allen; Christopher J Earley; William G Ondo; Lan Xiong; Jacques Montplaisir; Ziv Gan-Or; Markus Perola; Pavel Vodicka; Christian Dina; Andre Franke; Lukas Tittmann; Alexandre F R Stewart; Svati H Shah; Christian Gieger; Annette Peters; Guy A Rouleau; Klaus Berger; Konrad Oexle; Emanuele Di Angelantonio; David A Hinds; Bertram Müller-Myhsok; Juliane Winkelmann; 23andMe Research Team; DESIR study group

doi:10.1016/S1474-4422(17)30327-7

Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

Lancet Neurol. 2017 Nov;16(11):898-907. doi: 10.1016/S1474-4422(17)30327-7.

Authors

Barbara Schormair¹, Chen Zhao¹, Steven Bell², Erik Tilch¹, Aaro V Salminen¹, Benno Pütz³, Yves Dauvilliers⁴, Ambra Stefani⁵, Birgit Högl⁵, Werner Poewe⁵, David Kemlink⁶, Karel Sonka⁶, Cornelius G Bachmann⁷, Walter Paulus⁸, Claudia Trenkwalder⁹, Wolfgang H Oertel¹⁰, Magdolna Hornyak¹¹, Maris Teder-Laving¹², Andres Metspalu¹², Georgios M Hadjigeorgiou¹³, Olli Polo¹⁴, Ingo Fietze¹⁵, Owen A Ross¹⁶, Zbigniew Wszolek¹⁷, Adam S Butterworth¹⁸, Nicole Soranzo¹⁹, Willem H Ouwehand²⁰, David J Roberts²¹, John Danesh²², Richard P Allen²³, Christopher J Earley²³, William G Ondo²⁴, Lan Xiong²⁵, Jacques Montplaisir²⁶, Ziv Gan-Or²⁷, Markus Perola²⁸, Pavel Vodicka²⁹, Christian Dina³⁰, Andre Franke³¹, Lukas Tittmann³², Alexandre F R Stewart³³, Svati H Shah³⁴, Christian Gieger³⁵, Annette Peters³⁶, Guy A Rouleau³⁷, Klaus Berger³⁸, Konrad Oexle¹, Emanuele Di Angelantonio³⁹, David A Hinds⁴⁰, Bertram Müller-Myhsok⁴¹, Juliane Winkelmann⁴²; 23andMe Research Team; DESIR study group

Collaborators

B Balkau, P Ducimetière, E Eschwège, F Rancière, F Alhenc-Gelas, Y Gallois, A Girault, F Fumeron, M Marre, R Roussel, F Bonnet, A Bonnefond, S Cauchi, P Froguel, J Cogneau, C Born, E Caces, M Cailleau, O Lantieri, J G Moreau, F Rakotozafy, J Tichet, S Vol, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, David A Hinds, Bethann S Hromatka, Karen E Huber, Aaron Kleinman, Nadia K Litterman, Matthew H McIntyre, Joanna L Mountain, Carrie Am Northover, Steven J Pitts, J Fah Sathirapongsasuti, Olga V Sazonova, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Y Tung, Vladimir Vacic, Catherine H Wilson

Affiliations

¹ Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
² National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
³ Max Planck Institute of Psychiatry, Munich, Germany.
⁴ Sleep-Wake Disorders Centre, Department of Neurology, Hôpital Gui-de-Chauliac, INSERM U1061, CHU Montpellier, France.
⁵ Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
⁶ Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic.
⁷ Department of Neurology, Paracelsus Klinik, Osnabrueck, Germany.
⁸ Department of Clinical Neurophysiology, University Medical Centre, Georg August University Göttingen, Göttingen, Germany.
⁹ Clinic for Neurosurgery, University Medical Centre, Georg August University Göttingen, Göttingen, Germany; Paracelsus-Elena Hospital, Centre of Parkinsonism and Movement Disorders, Kassel, Germany.
¹⁰ Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Department of Neurology, Philipps University Marburg, Marburg, Germany.
¹¹ Department of Neurology, University of Ulm, Ulm, Germany; Neuropsychiatry Centre Erding/München, Erding, Germany.
¹² Estonian Genome Centre, University of Tartu and Estonian Biocentre, Tartu, Estonia.
¹³ Laboratory of Neurogenetics, Department of Neurology, Faculty of Medicine, University of Thessaly, University Hospital of Larissa, Biopolis, Larissa, Greece.
¹⁴ Unesta Research Centre, Tampere, Finland; Department of Pulmonary Diseases, Tampere University Hospital, Tampere, Finland.
¹⁵ Department of Cardiology and Angiology, Centre of Sleep Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁶ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
¹⁷ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
¹⁸ National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, UK.
¹⁹ National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
²⁰ National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; NHS Blood and Transplant, Cambridge, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, UK; Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
²¹ NHS Blood and Transplant, Oxford, UK; Radcliffe Department of Medicine, BRC Haematology Theme and NHS Blood and Transplant, John Radcliffe Hospital, Headington, Oxford, UK; Department of Haematology and BRC Haematology Theme, Churchill Hospital, Oxford, UK.
²² National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, UK; Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
²³ Center for Restless Legs Study, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
²⁴ Department of Neurology, Methodist Neurological Institute, Houston, TX, USA.
²⁵ Laboratoire de Neurogénétique, Centre de Recherche, Institut Universitaire en Santé Mentale de Montréal, Montréal, QC, Canada; Département de Psychiatrie, Université de Montréal, Montréal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
²⁶ Département de Psychiatrie, Université de Montréal, Montréal, QC, Canada; Hôpital du Sacré-Coeur de Montréal, 67120, Center for Advanced Research in Sleep Medicine, Montréal, QC, Canada.
²⁷ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
²⁸ Department of Health, National Institute for Health and Welfare, Helsinki, Finland; Institute of Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
²⁹ Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
³⁰ Inserm UMR1087, CNRS UMR 6291, Institut du Thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, France.
³¹ Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
³² PopGen Biobank and Institute of Epidemiology, Christian Albrechts University Kiel, Kiel, Germany.
³³ John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada.
³⁴ Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
³⁵ Institute of Epidemiology II, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; German Centre for Diabetes Research (DZD), Neuherberg, Germany.
³⁶ Institute of Epidemiology II, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; German Centre for Diabetes Research (DZD), Neuherberg, Germany; German Centre for Cardiovascular Disease Research (DZHK), Berlin, Germany.
³⁷ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
³⁸ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
³⁹ National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; NHS Blood and Transplant, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, UK.
⁴⁰ 23andMe, Mountain View, CA, USA.
⁴¹ Max Planck Institute of Psychiatry, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
⁴² Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany; Neurologische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. Electronic address: [email protected].

Abstract

Background: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets.

Methods: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10^-8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest.

Findings: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1).

Interpretation: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations.

Funding: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

Publication types

Meta-Analysis
Review

MeSH terms

DNA-Binding Proteins / genetics
GPI-Linked Proteins / genetics
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study*
Humans
Nerve Tissue Proteins / genetics
Netrins
Restless Legs Syndrome / epidemiology*
Restless Legs Syndrome / genetics*
Semaphorins / genetics
Transcription Factors / genetics
White People

Substances

DNA-Binding Proteins
GPI-Linked Proteins
MYT1 protein, human
NTNG1 protein, human
Nerve Tissue Proteins
Netrins
Sema6d protein, mouse
Semaphorins
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding