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PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome

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Abstract

We identified association of restless legs syndrome (RLS) with PTPRD at 9p23–24 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czechia and Canada. Two independent SNPs in the 5′ UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, Pnominal/λ corrected = 5.91 × 10−10, odds ratio (OR) = 1.44; rs1975197, Pnominal/λ corrected = 5.81 × 10−9, OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.

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Figure 1: Association results for stages 1 and 2 over the chromosomal segment analyzed.

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Acknowledgements

We are grateful to all individuals who participated in this study. We wish to thank J. Favor, B. Pütz and K. Oexle for discussions and R. Feldmann, J. Golic, K. Junghans and B. Schmick 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 research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. 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. D.K. was supported by grant MSM0021620849, and J.V. and K.S. were supported by grant MSM0021620816. Recruitment of Czech controls was funded by grant IGA NR 8563-5, Ministry of Health of the Czech Republic.

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Author notes

  1. Barbara Schormair and David Kemlink: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, 85764, Germany

    Barbara Schormair, David Kemlink, Gertrud Eckstein, Peter Lichtner, Thomas Meitinger & Juliane Winkelmann

  2. Institute of Human Genetics, Technische Universität München, Munich, 81675, Germany

    Barbara Schormair, Peter Lichtner, Thomas Meitinger & Juliane Winkelmann

  3. Department of Neurology, 1st Medical Faculty, Charles University, Prague, 120 00, Czech Republic

    David Kemlink, Gertrud Eckstein, Jana Vávrová, Karel Sonka & Sona Nevsimalova

  4. Max Planck Institute of Psychiatry, Munich, 80804, Germany

    Darina Roeske, Stephan Ripke, Florian Holsboer, Bertram Müller-Myhsok & Juliane Winkelmann

  5. Centre d'excellence en neuromique, Hôpital Notre-Dame, Université de Montréal, Montréal, H2L 4M1, Québec, Canada

    Lan Xiong & Guy Rouleau

  6. Paracelsus-Elena-Hospital, Kassel, 34128, Germany

    Claudia Trenkwalder

  7. Department of Neurology, Medical University of Vienna, Vienna, 1090, Austria

    Alexander Zimprich

  8. Department of Neurology, Center of Nervous Diseases, Philipps University, Marburg, 35039, Germany

    Karin Stiasny-Kolster & Wolfgang Oertel

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

    Cornelius G Bachmann & Walter Paulus

  10. Department of Neurology, Innsbruck Medical University, Innsbruck, 6020, Austria

    Birgit Högl, Birgit Frauscher, Viola Gschliesser & Werner Poewe

  11. Neurologische Praxis, Berlin, 10969, Germany

    Ines Peglau

  12. Institute of Experimental Medicine, Czech Academy of Sciences, Prague, 140 00, Czech Republic

    Pavel Vodicka

  13. Centre d'étude du sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, H4J 1C5, Québec, Canada

    Jacques Montplaisir

  14. Centre de recherche en sciences neurologiques, Université de Montréal, Montréal, H4J 1C5, Québec, Canada

    Jacques Montplaisir

  15. Departments of Psychiatry and Human Genetics, McGill University, Douglas Hospital, Montreal, H4H 1R3, Quebec, Canada

    Gustavo Turecki

  16. Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Munich, 85764, Germany

    Christian Gieger, Thomas Illig & H-Erich Wichmann

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

    H-Erich Wichmann

  18. Neurologische Klinik und Poliklinik, Technische Universität München, Ismaninger Strasse 22, München, 81675, Germany

    Juliane Winkelmann

Authors
  1. Barbara Schormair
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  2. Darina Roeske
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  3. Gertrud Eckstein
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  4. Lan Xiong
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  5. Peter Lichtner
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  6. Stephan Ripke
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  7. Claudia Trenkwalder
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  8. Alexander Zimprich
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  9. Karin Stiasny-Kolster
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  10. Wolfgang Oertel
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  11. Cornelius G Bachmann
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  12. Walter Paulus
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  13. Birgit Högl
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  14. Birgit Frauscher
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  15. Viola Gschliesser
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  16. Werner Poewe
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  17. Ines Peglau
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  18. Pavel Vodicka
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  19. Jana Vávrová
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  20. Karel Sonka
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  21. Sona Nevsimalova
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  22. Jacques Montplaisir
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  23. Gustavo Turecki
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  24. Guy Rouleau
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  25. Christian Gieger
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  26. Thomas Illig
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  27. H-Erich Wichmann
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  28. Florian Holsboer
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  29. Bertram Müller-Myhsok
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  30. Thomas Meitinger
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  31. Juliane Winkelmann
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Contributions

Study design: B.M.-M., T.M., J.W. Recruitment and biobanking of RLS cases: C.T., A.Z., K.S.-K., W.O., C.G.B., W. Paulus, B.H., B.F., V.G., W. Poewe, I.P., T.M., J.W. Recruitment and biobanking of KORA controls: C.G., T.I., H.-E.W. Recruitment and biobanking of Canadian RLS cases and controls: L.X., J.M., G.T., G.R. Recruitment and biobanking of Czech RLS cases and controls: D.K., P.V., J.V., K.S., S.N. Affymetrix genotyping: B.S., G.E., P.L. Sequenom genotyping: B.S., D.K., P.L. Supervision of all markers typed: P.L., J.W. Statistical analysis: D.R., S.R., B.M.-M. Clustering of Affymetrix genotypes: D.R., S.R., B.M.-M. Manuscript writing: B.S., D.K., D.R., F.H., B.M.-M., T.M., J.W.

Corresponding authors

Correspondence to Thomas Meitinger or Juliane Winkelmann.

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Competing interests

B.S., P.L. B.M.-M., F.H., T.M. and J.W. filed a patent application (application no. 07007202.0-2401) at the European Patent Office. All other authors have no competing financial interests.

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Supplementary Methods, Supplementary Tables 1–6 (PDF 218 kb)

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Schormair, B., Kemlink, D., Roeske, D. et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet 40, 946–948 (2008). https://doi.org/10.1038/ng.190

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