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Original article
MEIS1 and BTBD9: genetic association with restless leg syndrome in end stage renal disease
  1. Barbara Schormair1,2,
  2. Jens Plag3,
  3. Maria Kaffe1,2,
  4. Nadine Groß4,
  5. Darina Czamara5,
  6. Walter Samtleben6,
  7. Peter Lichtner1,2,
  8. Andreas Ströhle3,
  9. Ioannis Stefanidis7,
  10. Andreas Vainas7,
  11. Efthimios Dardiotis8,
  12. George K Sakkas7,
  13. Christian Gieger9,
  14. Bertram Müller-Myhsok4,
  15. Thomas Meitinger1,2,
  16. Uwe Heemann10,
  17. Georgios M Hadjigeorgiou8,
  18. Konrad Oexle2,
  19. Juliane Winkelmann1,2,4
  1. 1Institute of Human Genetics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
  2. 2Institute of Human Genetics, Technische Universität München, Munich, Germany
  3. 3Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité – Universitätsmedizin Berlin, Berlin, Germany
  4. 4Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
  5. 5Max Planck Institute of Psychiatry, Munich, Germany
  6. 6Department of Internal Medicine, Nephrology Division, University of Munich – Klinikum Grosshadern, Munich, Germany
  7. 7Department of Nephrology, Faculty of Medicine, University of Thessaly, BIOPOLIS, Larissa, Greece
  8. 8Department of Neurology, Faculty of Medicine, University of Thessaly, BIOPOLIS, Larissa, Greece
  9. 9Institute of Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
  10. 10Department of Nephrology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
  1. Correspondence to Juliane Winkelmann, Klinik für Neurologie und Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München (TUM), Ismaninger Strasse 22, 81675 München, Germany; winkelmann{at}


Background Restless legs syndrome (RLS) is a sleep related movement disorder that occurs both in an idiopathic form and in symptomatic varieties. RLS is a frequent and distressing comorbidity in end stage renal disease (ESRD). For idiopathic RLS (iRLS), genetic risk factors have been identified, but their role in RLS in ESRD has not been investigated yet. Therefore, a case–control association study of these variants in ESRD patients was performed.

Methods The study genotyped 10 iRLS associated variants at four loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, and PTPRD, in two independent case–control samples from Germany and Greece using multiplex PCR and MALDI-TOF (matrix assisted laser desorption/ionisation time-of-flight) mass spectrometry. Statistical analysis was performed as logistic regression with age and gender as covariates. For the combined analysis a Cochran–Mantel–Haenszel test was applied.

Results The study included 200 RLS-positive and 443 RLS-negative ESRD patients in the German sample, and 141 and 393 patients, respectively, in the Greek sample. In the German sample, variants in MEIS1 and BTBD9 were associated with RLS in ESRD (Pnom≤0.004, ORs 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9 (Pnom≤0.08, ORs 1.41 and 1.33). In the combined analysis including all samples, BTBD9 was associated after correction for multiple testing (Pcorrected=0.0013, OR 1.47).

Conclusions This is the first demonstration of a genetic influence on RLS in ESRD patients with BTBD9 being significantly associated. The extent of the genetic predisposition could vary between different subgroups of RLS in ESRD.

  • Restless legs syndrome
  • end-stage renal disease
  • genetic association studies
  • movement disorders (other than Parkinson's)
  • renal medicine
  • genetic epidemiology

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: and

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  • BS and JP contributed equally.

  • Funding This study was supported in part (for GMH and ED) from University of Thessaly, Research Committee (Code 2845).

  • Competing interests WS has received lecture fees from Ortho Biotech, GE Health Care, Sanofi Aventis and Roche Pharma. TM, BMM, JW filed a patent regarding the publication Winkelmann et al 2007.

  • Ethics approval This study was conducted with the approval of the local ethics committees in Germany (Klinikum rechts der Isar, TU München) and in Greece (University of Thessaloniki).

  • Provenance and peer review Not commissioned; externally peer reviewed.