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Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions

Nature Genetics volume 39, pages 1000–1006 (2007)Cite this article

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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Figure 1: Study overview.
Figure 2: Extent of population stratification.
Figure 3: Genome-wide association study for RLS susceptibility loci.
Figure 4: Pairwise linkage disequilibrium diagrams for three RLS-associated loci.
Figure 5: Haplotype structure for MEIS1.

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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

  1. Bertram Müller-Myhsok and Thomas Meitinger: These authors contributed equally to this work.

Authors and Affiliations

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

    Juliane Winkelmann, Barbara Schormair, Peter Lichtner, Shapour Jalilzadeh, Gertrud Eckstein, Stephanie Hauk & Thomas Meitinger

  2. Max Planck Institute of Psychiatry, Munich, D-80804, Germany

    Juliane Winkelmann, Stephan Ripke, Stephany Fulda, Benno Pütz, Florian Holsboer & Bertram Müller-Myhsok

  3. Technical University, Institute of Human Genetics, Munich, D-81675, 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, Kassel, 34128, Germany

    Claudia Trenkwalder

  6. Neurological Department, Medical University of Vienna, Vienna, 1090, Austria

    Alexander Zimprich

  7. Department of Neurology, Philipps University Marburg, Marburg, 35039, Germany

    Karin Stiasny-Kolster & Wolfgang Oertel

  8. Department of Clinical Neurophysiology, University of Göttingen, Göttingen, 37070, Germany

    Cornelius G Bachmann & Walter Paulus

  9. Neurologische Praxis, Berlin, 10969, Germany

    Ines Peglau

  10. Neurologische Praxis Sendlingerstrasse, Munich, 80331, 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, H4H 1R3, Quebec, Canada

    Gustavo Turecki

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

    Christian Gieger, Thomas Illig & H-Erich Wichmann

  15. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, 81377, Germany

    H-Erich Wichmann

Authors
  1. Juliane Winkelmann
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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.

Corresponding authors

Correspondence to Juliane Winkelmann or Thomas Meitinger.

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Competing interests

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

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Winkelmann, J., Schormair, B., Lichtner, P. et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 39, 1000–1006 (2007). https://doi.org/10.1038/ng2099

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