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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. A questionnaire study of 138 patients with restless legs sydrome: the 'night-walkers' survey. Neurology 46, 92–95 (1996).

  2. 2.

    et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 4, 101–119 (2003).

  3. 3.

    , & Prevalence and correlates of restless legs syndrome symptoms in the Wisconsin Sleep Cohort. Sleep Med. 7, 545–552 (2006).

  4. 4.

    , , , & The restless legs syndrome. Prog. Neurobiol. 77, 139–165 (2005).

  5. 5.

    et al. Genetics of restless legs syndrome (RLS): state-of-the-art and future directions. Mov. Disord., published online 7 June 2007 (doi:10.1002/mds.21587).

  6. 6.

    , & in Restless Legs Syndrome. Diagnosis and Treatment (ed. Ondo,W.G.) 111–123 (Informa Healthcare, New York, 2007).

  7. 7.

    et al. Family-based association study of the restless legs syndrome loci 2 and 3 in a European population. Mov. Disord. 22, 207–212 (2007).

  8. 8.

    , , & MONICA/KORA Study Group KORA-gen-resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 67, S26–S30 (2005).

  9. 9.

    et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat. Genet. 37, 1243–1246 (2005).

  10. 10.

    , , & The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev. Biol. 280, 307–320 (2005).

  11. 11.

    et al. Xmeis1, a protooncogene involved in specifying neural crest cell fate in Xenopus embryos. Oncogene 20, 1329–1342 (2001).

  12. 12.

    et al. Conserved regulation of proximodistal limb axis development by Meis/Hth. Nature 402, 425–429 (1999).

  13. 13.

    , , , & Some children with growing pains may actually have restless legs syndrome. Sleep 27, 767–773 (2004).

  14. 14.

    , , & A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity. Cell 123, 477–491 (2005).

  15. 15.

    , , , & Periodic limb movements in sleep. State-dependent excitability of the spinal flexor reflex. Neurology 54, 1609–1615 (2000).

  16. 16.

    Allen Institute for Brain Science. Allen Brain Atlas. (2004).

  17. 17.

    , , , & Sequence and structural analysis of BTB domain proteins. Genome Biol. 6, R82 (2005).

  18. 18.

    , , & Pattern formation in the limbs of Drosophila: bric à brac is expressed in both a gradient and a wave-like pattern and is required for specification and proper segmentation of the tarsus. Development 119, 799–812 (1993).

  19. 19.

    et al. Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells. EMBO Rep. 2, 829–834 (2001).

  20. 20.

    , , & Neuroprotective role of ERK1/2 and ERK5 in a dopaminergic cell line under basal conditions and in response to oxidative stress. J. Neurosci. Res. 84, 1367–1375 (2006).

  21. 21.

    , & Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34, 535–549 (2002).

  22. 22.

    , , & Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association. Nat. Genet. 38, 209–213 (2006).

  23. 23.

    , & Why population attributable fractions can sum to more than one. Am. J. Prev. Med. 26, 243–249 (2004).

  24. 24.

    WTCCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  25. 25.

    , , & A method to address differential bias in genotyping in large–scale association studies. Plos Genetics 3, e74 10.1371/journal.pgen.0030074 (2007).

  26. 26.

    , , & Haploview: analysis and visualisation of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

  27. 27.

    , & Population structure and Eigenanalysis. Plos Genetics 2, e190 (2006).

  28. 28.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

  29. 29.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  30. 30.

    UNPHASED user guide. Technical Report 2006/5. (MRC Biostatistics Unit, Cambridge, UK, 2006).

Download references


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.


  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


  1. Search for Juliane Winkelmann in:

  2. Search for Barbara Schormair in:

  3. Search for Peter Lichtner in:

  4. Search for Stephan Ripke in:

  5. Search for Lan Xiong in:

  6. Search for Shapour Jalilzadeh in:

  7. Search for Stephany Fulda in:

  8. Search for Benno Pütz in:

  9. Search for Gertrud Eckstein in:

  10. Search for Stephanie Hauk in:

  11. Search for Claudia Trenkwalder in:

  12. Search for Alexander Zimprich in:

  13. Search for Karin Stiasny-Kolster in:

  14. Search for Wolfgang Oertel in:

  15. Search for Cornelius G Bachmann in:

  16. Search for Walter Paulus in:

  17. Search for Ines Peglau in:

  18. Search for Ilonka Eisensehr in:

  19. Search for Jacques Montplaisir in:

  20. Search for Gustavo Turecki in:

  21. Search for Guy Rouleau in:

  22. Search for Christian Gieger in:

  23. Search for Thomas Illig in:

  24. Search for H-Erich Wichmann in:

  25. Search for Florian Holsboer in:

  26. Search for Bertram Müller-Myhsok in:

  27. Search for Thomas Meitinger in:


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.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–9.

About this article

Publication history






Further reading