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

References

  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. http://www.brain-map.org (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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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.

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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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  2. Barbara Schormair
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  3. Peter Lichtner
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  4. Stephan Ripke
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  5. Lan Xiong
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  6. Shapour Jalilzadeh
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  7. Stephany Fulda
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  8. Benno Pütz
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  9. Gertrud Eckstein
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  10. Stephanie Hauk
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  11. Claudia Trenkwalder
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  12. Alexander Zimprich
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  13. Karin Stiasny-Kolster
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  14. Wolfgang Oertel
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  15. Cornelius G Bachmann
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  16. Walter Paulus
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  17. Ines Peglau
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  18. Ilonka Eisensehr
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  19. Jacques Montplaisir
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  20. Gustavo Turecki
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  21. Guy Rouleau
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  22. Christian Gieger
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  23. Thomas Illig
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  24. H-Erich Wichmann
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  25. Florian Holsboer
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  26. Bertram Müller-Myhsok
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  27. Thomas Meitinger
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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 toJuliane 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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