Evidence map›Paper›PMID 29029846›Full record

SynthesisThe Lancet. Neurology2017

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 and 43 more

Open access · hybridAbstract readMeta-AnalysisReview
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in The Lancet. Neurology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 108 papers, 14 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
108citing papers in PubMed, 14 pooled it
17.3field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

108 citing papers in PubMed, 14 syntheses or guidelines pooled it, 237 citations in OpenAlex.

  1. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline.Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine · 2025
    Guideline
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  7. Putative Animal Models of Restless Legs Syndrome: A Systematic Review and Evaluation of Their Face and Construct Validity.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023
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  15. Review
  16. Emerging genetics of sleep and circadian disorders.Current opinion in pediatrics · 2026
    Article
  17. Article
  18. Polygenic risk scores in neurological disorders: restless legs syndrome as a translational model.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2026
    Article
  19. Article
  20. Review

48 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

53 authors at 20 institutions in 10 countries.

Barbara SchormairInstitute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
Chen ZhaoInstitute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
Steven BellNational 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.
Erik TilchInstitute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
Aaro V SalminenInstitute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
Benno PützMax Planck Institute of Psychiatry, Munich, Germany.
Yves DauvilliersSleep-Wake Disorders Centre, Department of Neurology, Hôpital Gui-de-Chauliac, INSERM U1061, CHU Montpellier, France.
Ambra StefaniDepartment of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Birgit HöglDepartment of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Werner PoeweDepartment of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
David KemlinkDepartment of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic.
Karel SonkaDepartment of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic.
Cornelius G BachmannDepartment of Neurology, Paracelsus Klinik, Osnabrueck, Germany.
Walter PaulusDepartment of Clinical Neurophysiology, University Medical Centre, Georg August University Göttingen, Göttingen, Germany.
Claudia TrenkwalderClinic for Neurosurgery, University Medical Centre, Georg August University Göttingen, Göttingen, Germany; Paracelsus-Elena Hospital, Centre of Parkinsonism and Movement Disorders, Kassel, Germany.
Wolfgang H OertelInstitute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Department of Neurology, Philipps University Marburg, Marburg, Germany.
Magdolna HornyakDepartment of Neurology, University of Ulm, Ulm, Germany; Neuropsychiatry Centre Erding/München, Erding, Germany.
Maris Teder-LavingEstonian Genome Centre, University of Tartu and Estonian Biocentre, Tartu, Estonia.
Andres MetspaluEstonian Genome Centre, University of Tartu and Estonian Biocentre, Tartu, Estonia.
Georgios M HadjigeorgiouLaboratory of Neurogenetics, Department of Neurology, Faculty of Medicine, University of Thessaly, University Hospital of Larissa, Biopolis, Larissa, Greece.
Olli PoloUnesta Research Centre, Tampere, Finland; Department of Pulmonary Diseases, Tampere University Hospital, Tampere, Finland.
Ingo FietzeDepartment of Cardiology and Angiology, Centre of Sleep Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Owen A RossDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Zbigniew WszolekDepartment of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Adam S ButterworthNational 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.
Nicole SoranzoNational 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.
Willem H OuwehandNational 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.
David J RobertsNHS 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.
John DaneshNational 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.
Richard P AllenCenter for Restless Legs Study, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Christopher J EarleyCenter for Restless Legs Study, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
William G OndoDepartment of Neurology, Methodist Neurological Institute, Houston, TX, USA.
Lan XiongLaboratoire 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.
Jacques MontplaisirDépartement 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.
Ziv Gan-OrDepartment of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada; Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
Markus PerolaDepartment of Health, National Institute for Health and Welfare, Helsinki, Finland; Institute of Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
Pavel VodickaDepartment 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.
Christian DinaInserm UMR1087, CNRS UMR 6291, Institut du Thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, France.
Andre FrankeInstitute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
Lukas TittmannPopGen Biobank and Institute of Epidemiology, Christian Albrechts University Kiel, Kiel, Germany.
Alexandre F R StewartJohn and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada.
Svati H ShahDepartment of Medicine, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
Christian GiegerInstitute 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.
Annette PetersInstitute 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.
Guy A RouleauDepartment 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.
Klaus BergerInstitute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
Konrad OexleInstitute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
Emanuele Di AngelantonioNational 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.
David A Hinds23andMe, Mountain View, CA, USA.
Bertram Müller-MyhsokMax Planck Institute of Psychiatry, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Juliane WinkelmannInstitute 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.
23andMe Research Team
DESIR study group
Helmholtz Zentrum München · DEGenomics (United Kingdom) · GBGeneral University Hospital in Prague · CZMunich Cluster for Systems Neurology · DE23andMe (United States) · USBritish Heart Foundation · GBChristian-Albrechts-Universität zu Kiel · DEEstonian Biocentre · EEJohns Hopkins University · USKlinikum rechts der Isar · DEMayo Clinic in Florida · USMontreal Neurological Institute and Hospital · CAUniversität Innsbruck · ATAddenbrooke's Hospital · GBCharité - Universitätsmedizin Berlin · DECzech Academy of Sciences · CZDeutsches Diabetes-Zentrum e.V. · DEDuke University · USHôpital du Sacré-Cœur de Montréal · CAHôpital Gui de Chauliac · FR

Funding

Neuropathology CoreP50NS072187 · NINDS · MAYO CLINIC JACKSONVILLE · PI DICKSON, DENNIS WILLIAM · 2010 to 2017
$8.7M
British Heart Foundation CH/12/2/29428British Heart Foundation RG/08/014/24067British Heart Foundation RG/13/13/30194British Heart Foundation RG/16/4/32218Department of Health RP-PG-0310-1004Medical Research Council G0800270Medical Research Council MR/L003120/1Medical Research Council MR/P013880/1Medical Research Council MR/P02811X/1NINDS NIH HHS P50 NS072187Wellcome Trust
6 · The paper itself

Abstract

backgroundRestless 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.

methodsIn 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

findingsWe 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).

interpretationIdentification 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.

fundingDeutsche 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.

Indexed as

Genome-Wide Association StudyDNA-Binding ProteinsGenetic Predisposition to DiseaseGPI-Linked ProteinsHumansNerve Tissue ProteinsNetrinsRestless Legs SyndromeSemaphorinsTranscription FactorsWhite PeopleDNA-Binding ProteinsGPI-Linked ProteinsMYT1 protein, humanNerve Tissue ProteinsNetrinsNTNG1 protein, humanSema6d protein, mouseSemaphorinsTranscription Factors

Identifiers

PMID29029846
PMCPMC5755468
OpenAlexW2764285200

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.