• A Corrigendum to this article was published on 29 March 2011

This article has been updated


Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15–25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 × 10−8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 × 10−43) and DRB1*1301-DQB1*0603 (P < 3 × 10−7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 × 10−14). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

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Change history

  • 27 October 2010

    In the version of this article initially published, the name of author Peter Vollenweider was incorrectly written as Peter Vollenwider. Also, Claudio Bassetti’s affiliation was incorrectly listed as Neurocentro (Ente ospedaliero cantonale) della Svizzera Italiana, Ospedale Civico, Lugano, Switzerland. His correct affiliation is Department of Neurology, University Hospital Zurich, Zurich, Switzerland. These errors have been corrected in the HTML and PDF versions of the article.


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We thank all the subjects for their generous participation in this study; our colleagues K. Harshman and O. Hagenbuchle and the staff of the Lausanne DNA array facility for their expert technical assistance; and F. Canellas from the University Hospital Son Dureta, Palma-Spain and P. Young from the Department of Neurology, University Hospital Muenster-Germany for providing additional data on narcolepsy patients. Support for this research was provided by the French Ministry of Research and Higher Education, Project Agence Nationale de la Recherche-07-MRAR (France), PHRC 2007-P070138 (France), European Narcolepsy Network, an unrestricted grant from UCB Pharma S.A. (Belgium), the University and the State of Vaud (Switzerland), the Swiss National Science Foundation (grants 3100AO-108478/2, 3100AO-116323/1 and 310000-112552/1), the European Framework Project 6 (EuroDia and the AnEuploidy projects) and GlaxoSmithKline (which sponsored in part the CoLaus study). S.B. is funded by the Giorgi-Cavaglieri Foundation and the Leenaards Foundation. Special thanks to T. Johnson for his valuable advice on data analysis. The computations were performed in part at the Vital-IT center for high-performance computing of the Swiss Institute of Bioinformatics. This study was conducted on behalf of the European Narcolepsy Network.

Author information

Author notes

    • Hyun Hor
    •  & Zoltán Kutalik

    These authors contributed equally to this work.


  1. Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

    • Hyun Hor
    • , Brice Petit
    • , Corinne Pfister
    • , Julie Vienne Bürki
    • , Gérard Didelot
    •  & Mehdi Tafti
  2. Institut National de la Santé et de la Recherche Médicale U888, Montpellier, France.

    • Hyun Hor
    •  & Yves Dauvilliers
  3. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Zoltán Kutalik
    • , Armand Valsesia
    • , Jacques S Beckmann
    •  & Sven Bergmann
  4. Swiss Institute of Bioinformatics, Lausanne, Switzerland.

    • Zoltán Kutalik
    • , Armand Valsesia
    •  & Sven Bergmann
  5. National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Gui-de-Chauliac Hospital, Montpellier, France.

    • Yves Dauvilliers
    •  & Michel Billiard
  6. Ludwig Institute for Cancer Research, Lausanne, Switzerland.

    • Armand Valsesia
  7. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Gert J Lammers
    •  & Claire E H M Donjacour
  8. Neurology Service, Hospital Clínic, Institut d'Investigació Biomèdiques August Pi i Sunyer, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain.

    • Alex Iranzo
    •  & Joan Santamaria
  9. Sleep and Epilepsy Unit, Clinical Neurophysiology Department, Gregorio Marañón University Hospital, Madrid, Spain.

    • Rosa Peraita Adrados
  10. Histocompatibility, Blood Center of the Community of Madrid, Madrid, Spain.

    • José L Vicario
  11. Sleep Medicine Center 'Kempenhaeghe', Heeze, The Netherlands.

    • Sebastiaan Overeem
  12. Department of Neurology, Donders Institute for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Sebastiaan Overeem
  13. National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Sleep Disorders Unit, Pitié-Salpêtrière Hospital, Paris, France.

    • Isabelle Arnulf
  14. Institut National de la Santé et de la Recherche Médicale U543, Pitié-Salpêtrière Hospital, Paris, France.

    • Ioannis Theodorou
  15. Department of Clinical Neurophysiology, University of Copenhagen, Glostrup, Denmark.

    • Poul Jennum
    •  & Stine Knudsen
  16. Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

    • Claudio Bassetti
  17. Abteilung Klinische Neurophysiologie, Inselspital, Bern, Switzerland.

    • Johannes Mathis
  18. Pediatric Sleep Center, National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Child and Adolescent Psychopathology, Robert Debré Hospital, Paris VII University, Paris, France.

    • Michel Lecendreux
  19. Hephata-Clinic for Neurology, Schwalmstadt-Treysa, Germany.

    • Geert Mayer
  20. Sleep Disorders and Research Center, Department of Psychiatry and Psychotherapy, University Hospital Regensburg, Regensburg, Germany.

    • Peter Geisler
  21. Unidad de Sueño, Servicio Neurofisiología Clínica, Hospital Universitario La Fe, Valencia, Spain.

    • Antonio Benetó
  22. Immunology Service, Institut d'Investigació Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona, Spain.

    • Guadalupe Ercilla
  23. Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands.

    • Willem Verduijn
    •  & Frans H J Claas
  24. Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

    • Peter Vollenweider
    •  & Gerard Waeber
  25. Division of Genetics, Research and Development, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

    • Dawn M Waterworth
    •  & Vincent Mooser
  26. Center for Investigation and Research in Sleep, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

    • Raphaël Heinzer
    •  & Mehdi Tafti
  27. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

    • Jacques S Beckmann


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Participant recruitment and clinical assessment: Y.D., G.J.L., C.E.H.M.D., A.I., J.S., R.P.A., J.L.V., S.O., I.A., I.T., P.J., S.K., C.B., J.M., M.L., G.M., P.G., A.B., M.B., G.E., F.H.J.C., P.V., G.W., D.M.W., V.M. and R.H. Sample processing and genotyping: H.H., J.L.V., I.T., B.P., C.P., J.V.B., G.D., G.E., W.V. and F.H.J.C. Data analysis: Z.K., H.H., A.V. and M.T. Study design and management: Y.D., G.J.L., J.S.B., S.B. and M.T. Manuscript preparation: H.H., Z.K., Y.D., J.S.B., S.B. and M.T. CoLaus control data: P.V., G.W., D.M.W. and V.M. All authors contributed to the final version of the manuscript.

Competing interests

Y.D., G.J.L., P.J., C.B., M.L., G.M., S.O., J.M. and M.T. declare having received honoraria as speakers and/or members of the advisory board of UCB Pharma S.A. (Belgium). P.G. has received honoraria as a speaker and member of the XYREM advisory board from UCB GmbH and an honorarium as a speaker from Cephalon GmbH (Germany). R.H. received unrestricted grants from ResMed P.V., and G.W. received an unrestricted grant from GSK for the CoLaus project. V.M. and D.M.W. are full-time employees of GlaxoSmithKline, a pharmaceutical company.

Corresponding author

Correspondence to Mehdi Tafti.

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