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


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.


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

    Article  CAS  Google Scholar 

  2. Allen, R.P. 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).

    Article  Google Scholar 

  3. Winkelman, J.W., Finn, L. & Young, T. Prevalence and correlates of restless legs syndrome symptoms in the Wisconsin Sleep Cohort. Sleep Med. 7, 545–552 (2006).

    Article  Google Scholar 

  4. Barrière, G., Cazalets, J.R., Bioulac, B., Tison, F. & Ghorayeb, I. The restless legs syndrome. Prog. Neurobiol. 77, 139–165 (2005).

    Article  Google Scholar 

  5. Winkelmann, J. 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).

    Article  Google Scholar 

  6. Rao, S., Winkelmann, J. & Wang, Q.K. in Restless Legs Syndrome. Diagnosis and Treatment (ed. Ondo,W.G.) 111–123 (Informa Healthcare, New York, 2007).

    Google Scholar 

  7. Kemlink, D. 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).

    Article  Google Scholar 

  8. Wichmann, H.E., Gieger, C., Illig, T. & MONICA/KORA Study Group KORA-gen-resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 67, S26–S30 (2005).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Azcoitia, V., Aracil, M., Martinez, A.C. & Torres, M. The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev. Biol. 280, 307–320 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Rajaram, S.S., Walters, A.S., England, S.J., Mehta, D. & Nizam, F. Some children with growing pains may actually have restless legs syndrome. Sleep 27, 767–773 (2004).

    Google Scholar 

  14. Dasen, J.S., Tice, B.C., Brenner-Morton, S. & Jessel, T.M. A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity. Cell 123, 477–491 (2005).

    Article  CAS  Google Scholar 

  15. Bara-Jimenez, W., Aksu, M., Graham, B., Sato, S. & Hallett, M. Periodic limb movements in sleep. State-dependent excitability of the spinal flexor reflex. Neurology 54, 1609–1615 (2000).

    Article  CAS  Google Scholar 

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

  17. Stogios, P.J., Downs, G.S., Jauhal, J.J., Nandra, S.K. & Prive, G.G. Sequence and structural analysis of BTB domain proteins. Genome Biol. 6, R82 (2005).

    Article  Google Scholar 

  18. Godt, D., Couderc, J.L., Cramton, S.E. & Laski, F.A. 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).

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Cavanaugh, J.E., Jaumotte, J.D., Lakoski, J.M. & Zigmond, M.J. 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).

    Article  CAS  Google Scholar 

  21. Gross, M.K., Dottori, M. & Goulding, M. Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34, 535–549 (2002).

    Article  CAS  Google Scholar 

  22. Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association. Nat. Genet. 38, 209–213 (2006).

    Article  CAS  Google Scholar 

  23. Rowe, A.K., Powell, K.E. & Flanders, W.D. Why population attributable fractions can sum to more than one. Am. J. Prev. Med. 26, 243–249 (2004).

    Article  Google Scholar 

  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. Plagnol, V., Cooper, A.D., Todd, J.A. & Clayton, D.G. A method to address differential bias in genotyping in large–scale association studies. Plos Genetics 3, e74 10.1371/journal.pgen.0030074 (2007).

    Article  CAS  Google Scholar 

  26. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualisation of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  27. Patterson, N., Price, A.L. & Reich, D. Population structure and Eigenanalysis. Plos Genetics 2, e190 (2006).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  Google Scholar 

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

    Google Scholar 

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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.

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Authors and Affiliations



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.

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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).

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