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.

Biomedical Centre Faculty of Medicine in Pilsen Charles University Prague Pilsen Czech Republic

British Heart Foundation Centre of Excellence Division of Cardiovascular Medicine Addenbrooke's Hospital Cambridge UK

Center for Restless Legs Study Department of Neurology Johns Hopkins University Baltimore MD USA

Centre Hospitalier Universitaire Nantes Université de Nantes France

Clinic for Neurosurgery University Medical Centre Georg August University Göttingen Göttingen Germany

Département de Psychiatrie Université de Montréal Montréal QC Canada

Department of Cardiology and Angiology Centre of Sleep Medicine Charité Universitätsmedizin Berlin Berlin Germany

Department of Clinical Neurophysiology University Medical Centre Georg August University Göttingen Göttingen Germany

Department of Haematology and BRC Haematology Theme Churchill Hospital Oxford UK

Department of Haematology University of Cambridge Cambridge Biomedical Campus Cambridge UK

Department of Health National Institute for Health and Welfare Helsinki Finland

Department of Human Genetics McGill University Montréal QC Canada

Department of Human Genetics Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton UK

Department of Medicine Duke University School of Medicine Durham NC USA

Department of Molecular Biology of Cancer Institute of Experimental Medicine Academy of Science of Czech Republic Prague Czech Republic

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine and General University Hospital Prague Charles University Prague Czech Republic

Department of Neurology and Neurosurgery McGill University Montréal QC Canada

Department of Neurology Mayo Clinic Jacksonville FL USA

Department of Neurology Medical University of Innsbruck Innsbruck Austria

Department of Neurology Methodist Neurological Institute Houston TX USA

Department of Neurology Paracelsus Klinik Osnabrueck Germany

Department of Neurology Philipps University Marburg Marburg Germany

Department of Neurology University of Ulm Ulm Germany

Department of Neuroscience Mayo Clinic Jacksonville FL USA

Department of Pulmonary Diseases Tampere University Hospital Tampere Finland

Duke Clinical Research Institute Duke University School of Medicine Durham NC USA

Estonian Genome Centre University of Tartu and Estonian Biocentre Tartu Estonia

German Centre for Cardiovascular Disease Research Berlin Germany

German Centre for Diabetes Research Neuherberg Germany

Hôpital du Sacré Coeur de Montréal 67120 Center for Advanced Research in Sleep Medicine Montréal QC Canada

Inserm UMR1087 CNRS UMR 6291 Institut du Thorax Nantes France

Institute of Clinical Molecular Biology Kiel University Kiel Germany

Institute of Epidemiology 2 Helmholtz Zentrum München German Research Centre for Environmental Health Neuherberg Germany

Institute of Epidemiology and Social Medicine University of Münster Münster Germany

Institute of Human Genetics Technische Universität München Munich Germany

Institute of Molecular Medicine FIMM University of Helsinki Helsinki Finland

Institute of Neurogenomics Helmholtz Zentrum München German Research Centre for Environmental Health Neuherberg Germany

Institute of Translational Medicine University of Liverpool Liverpool UK

John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre University of Ottawa Heart Institute Ottawa ON Canada

Laboratoire de Neurogénétique Centre de Recherche Institut Universitaire en Santé Mentale de Montréal Montréal QC Canada

Laboratory of Neurogenetics Department of Neurology Faculty of Medicine University of Thessaly University Hospital of Larissa Biopolis Larissa Greece

Max Planck Institute of Psychiatry Munich Germany

Me Mountain View CA USA

Montreal Neurological Institute McGill University Montréal QC Canada

MRC BHF Cardiovascular Epidemiology Unit Department of Public Health and Primary Care Strangeways Research Laboratory University of Cambridge Cambridge UK

Munich Cluster for Systems Neurology Munich Germany

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

National Institute for Health Research Cambridge Biomedical Research Centre Cambridge UK

Neurologische Klinik und Poliklinik Klinikum rechts der Isar der Technischen Universität München Munich Germany

Neuropsychiatry Centre Erding München Erding Germany

NHS Blood and Transplant Cambridge UK

NHS Blood and Transplant Oxford UK

Paracelsus Elena Hospital Centre of Parkinsonism and Movement Disorders Kassel Germany

PopGen Biobank and Institute of Epidemiology Christian Albrechts University Kiel Kiel Germany

Radcliffe Department of Medicine BRC Haematology Theme and NHS Blood and Transplant John Radcliffe Hospital Headington Oxford UK

Research Unit of Molecular Epidemiology Helmholtz Zentrum München German Research Centre for Environmental Health Neuherberg Germany

Sleep Wake Disorders Centre Department of Neurology Hôpital Gui de Chauliac INSERM U1061 CHU Montpellier France

Unesta Research Centre Tampere Finland

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$a Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis / $c B. Schormair, C. Zhao, S. Bell, E. Tilch, AV. Salminen, B. Pütz, Y. Dauvilliers, A. Stefani, B. Högl, W. Poewe, D. Kemlink, K. Sonka, CG. Bachmann, W. Paulus, C. Trenkwalder, WH. Oertel, M. Hornyak, M. Teder-Laving, A. Metspalu, GM. Hadjigeorgiou, O. Polo, I. Fietze, OA. Ross, Z. Wszolek, AS. Butterworth, N. Soranzo, WH. Ouwehand, DJ. Roberts, J. Danesh, RP. Allen, CJ. Earley, WG. Ondo, L. Xiong, J. Montplaisir, Z. Gan-Or, M. Perola, P. Vodicka, C. Dina, A. Franke, L. Tittmann, AFR. Stewart, SH. Shah, C. Gieger, A. Peters, GA. Rouleau, K. Berger, K. Oexle, E. Di Angelantonio, DA. Hinds, B. Müller-Myhsok, J. Winkelmann, . , . ,

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$a 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.

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$a Zhao, Chen $u Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.

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$a Bell, Steven $u 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.

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$a Tilch, Erik $u Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.

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$a Salminen, Aaro V $u Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.

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$a Pütz, Benno $u Max Planck Institute of Psychiatry, Munich, Germany.

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$a Dauvilliers, Yves $u Sleep-Wake Disorders Centre, Department of Neurology, Hôpital Gui-de-Chauliac, INSERM U1061, CHU Montpellier, France.

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$a Stefani, Ambra $u Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

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$a Högl, Birgit $u Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

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$a Poewe, Werner $u Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

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$a Sonka, Karel $u Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic.

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$a Bachmann, Cornelius G $u Department of Neurology, Paracelsus Klinik, Osnabrueck, Germany.

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$a Trenkwalder, Claudia $u Clinic for Neurosurgery, University Medical Centre, Georg August University Göttingen, Göttingen, Germany; Paracelsus-Elena Hospital, Centre of Parkinsonism and Movement Disorders, Kassel, Germany.

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$a Oertel, Wolfgang H $u Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Department of Neurology, Philipps University Marburg, Marburg, Germany.

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$a Hornyak, Magdolna $u Department of Neurology, University of Ulm, Ulm, Germany; Neuropsychiatry Centre Erding/München, Erding, Germany.

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$a Teder-Laving, Maris $u Estonian Genome Centre, University of Tartu and Estonian Biocentre, Tartu, Estonia.

700    1_

$a Metspalu, Andres $u Estonian Genome Centre, University of Tartu and Estonian Biocentre, Tartu, Estonia.

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$a Hadjigeorgiou, Georgios M $u Laboratory of Neurogenetics, Department of Neurology, Faculty of Medicine, University of Thessaly, University Hospital of Larissa, Biopolis, Larissa, Greece.

700    1_

$a Polo, Olli $u Unesta Research Centre, Tampere, Finland; Department of Pulmonary Diseases, Tampere University Hospital, Tampere, Finland.

700    1_

$a Fietze, Ingo $u Department of Cardiology and Angiology, Centre of Sleep Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.

700    1_

$a Ross, Owen A $u Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

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$a Wszolek, Zbigniew $u Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.

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$a Butterworth, Adam S $u 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.

700    1_

$a Soranzo, Nicole $u 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.

700    1_

$a Ouwehand, Willem H $u 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.

700    1_

$a Roberts, David J $u 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.

700    1_

$a Danesh, John $u 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.

700    1_

$a Allen, Richard P $u Center for Restless Legs Study, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

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$a Earley, Christopher J $u Center for Restless Legs Study, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

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$a Ondo, William G $u Department of Neurology, Methodist Neurological Institute, Houston, TX, USA.

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$a Xiong, Lan $u 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.

700    1_

$a Montplaisir, Jacques $u 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.

700    1_

$a Gan-Or, Ziv $u Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.

700    1_

$a Perola, Markus $u Department of Health, National Institute for Health and Welfare, Helsinki, Finland; Institute of Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.

700    1_

$a Vodicka, Pavel $u 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.

700    1_

$a Dina, Christian $u Inserm UMR1087, CNRS UMR 6291, Institut du Thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, France.

700    1_

$a Franke, Andre $u Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.

700    1_

$a Tittmann, Lukas $u PopGen Biobank and Institute of Epidemiology, Christian Albrechts University Kiel, Kiel, Germany.

700    1_

$a Stewart, Alexandre F R $u John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada.

700    1_

$a Shah, Svati H $u Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.

700    1_

$a Gieger, Christian $u 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.

700    1_

$a Peters, Annette $u 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.

700    1_

$a Rouleau, Guy A $u 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.

700    1_

$a Berger, Klaus $u Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

700    1_

$a Oexle, Konrad $u Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.

700    1_

$a Di Angelantonio, Emanuele $u 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.

700    1_

$a Hinds, David A $u 23andMe, Mountain View, CA, USA.

700    1_

$a Müller-Myhsok, Bertram $u Max Planck Institute of Psychiatry, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

700    1_

$a Winkelmann, Juliane $u 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: juliane.winkelmann@tum.de.

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