Abstract

Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

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Acknowledgements

We are grateful to all patients who participated in this study. The authors also thank T.M. Strom, J. Favor, D. Vogt-Weisenhorn, W. Wurst and I. Tews for discussions and R. Feldmann, J. Golic, K. Junghans, B. Schmick, N. Trapp, M. Petzold, G. Fischer and M. Putz for technical assistance. We acknowledge L. Habersack, H. Rhese and J. Schmidt-Evers from the German RLS patient organization for supporting this study. Part of this work was financed by the National Genome Research Network (NGFN). The KORA study group consists of H.-E. Wichmann (speaker), R. Holle, J. John, T. Illig, C. Meisinger, A. Peters and their co-workers, who are responsible for the design and conduct of the KORA studies. The KORA (Cooperative Research in the Region of Augsburg) research project was initiated and financed by the National Research Centre for Environment and Health (GSF), which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. S.H. was partly supported by a grant from the German RLS patient organization. J.W. was partly supported by a grant form the Bavarian Ministry of Science, Culture and Art. The Canadian part of the study was supported by a Canadian Institutes of Health Research (CIHR) grant to G.R, J.M and G.T.

Author information

Author notes

    • Bertram Müller-Myhsok
    •  & Thomas Meitinger

    These authors contributed equally to this work.

Affiliations

  1. Institute of Human Genetics, GSF National Research Center of Environment and Health, D-85764 Neuherberg, Munich, Germany.

    • Juliane Winkelmann
    • , Barbara Schormair
    • , Peter Lichtner
    • , Shapour Jalilzadeh
    • , Gertrud Eckstein
    • , Stephanie Hauk
    •  & Thomas Meitinger
  2. Max Planck Institute of Psychiatry, D-80804 Munich, Germany.

    • Juliane Winkelmann
    • , Stephan Ripke
    • , Stephany Fulda
    • , Benno Pütz
    • , Florian Holsboer
    •  & Bertram Müller-Myhsok
  3. Technical University, Institute of Human Genetics, D-81675 Munich, Germany.

    • Juliane Winkelmann
    • , Barbara Schormair
    • , Peter Lichtner
    • , Shapour Jalilzadeh
    • , Gertrud Eckstein
    • , Stephanie Hauk
    •  & Thomas Meitinger
  4. Laboratoire d'étude des maladies du cerveau, Centre de recherche du CHUM, Hôpital Notre-Dame, Université de Montréal, Montréal, Québec H2L 4M1, Canada.

    • Lan Xiong
    •  & Guy Rouleau
  5. Paracelsus-Elena-Hospital, 34128 Kassel, Germany.

    • Claudia Trenkwalder
  6. Neurological Department, Medical University of Vienna, 1090 Vienna, Austria.

    • Alexander Zimprich
  7. Philipps University Marburg, Department of Neurology, 35039 Marburg, Germany.

    • Karin Stiasny-Kolster
    •  & Wolfgang Oertel
  8. University of Göttingen, Department of Clinical Neurophysiology, 37070 Göttingen, Germany.

    • Cornelius G Bachmann
    •  & Walter Paulus
  9. Neurologische Praxis, 10969 Berlin, Germany.

    • Ines Peglau
  10. Neurologische Praxis Sendlingerstrasse, 80331 Munich, Germany.

    • Ilonka Eisensehr
  11. Centre d'étude du sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, Québec H4J 1C5, Canada.

    • Jacques Montplaisir
  12. Centre de recherche en sciences neurologiques, Université de Montréal, Montréal, Québec H4J 1C5, Canada.

    • Jacques Montplaisir
  13. Departments of Psychiatry and Human Genetics, McGill University, Douglas Hospital, Montreal, Quebec H4H 1R3, Canada.

    • Gustavo Turecki
  14. Institute of Epidemiology, GSF National Research Center for Environment and Health, 85764 Neuherberg, Munich, Germany.

    • Christian Gieger
    • , Thomas Illig
    •  & H-Erich Wichmann
  15. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.

    • H-Erich Wichmann

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Contributions

Study design: J.W., P.L., G.R., F.H., B.M.-M., T.M.; recruitment and biobanking of individuals with RLS: J.W., S.H., C.T., A.Z., K.S.-K., W.O., C.B., W.P., I.P., I.E., T.M.; recruitment and biobanking of KORA controls: C.G., T.I., H.-E.W.; recruitment and biobanking of Canadian affected individuals and controls: L.X., J.M., G.T., G.R.; Affymetrix genotyping: B.S., P.L., G.E.; Sequenom genotyping: B.S., P.L., S.J.; supervision of typing of all markers: J.W., P.L.; software development and data processing: S.R.,B.P.; statistical analysis: S.R., B.P., B.M.-M.; clustering of Affymetrix genotypes: S.R., B.M.-M.; manuscript writing: J.W., B.S., S.F., L.X., F.H., B.M.-M., T.M.

Competing interests

J.W., B.S., P.L., B.M.-M., F.H. and T.M. have filed a patent application.

Corresponding authors

Correspondence to Juliane Winkelmann or Thomas Meitinger.

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DOI

https://doi.org/10.1038/ng2099

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