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Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

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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Figure 1: Manhattan plots of association results.

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.


  1. Tafti, M., Dauvilliers, Y. & Overeem, S. Narcolepsy and familial advanced sleep-phase syndrome: molecular genetics of sleep disorders. Curr. Opin. Genet. Dev. 17, 222–227 (2007).

    Article  CAS  Google Scholar 

  2. Mignot, E. et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am. J. Hum. Genet. 68, 686–699 (2001).

    Article  CAS  Google Scholar 

  3. Nishino, S., Ripley, B., Overeem, S., Lammers, G.J. & Mignot, E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39–40 (2000).

    Article  CAS  Google Scholar 

  4. Peyron, C. et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med. 6, 991–997 (2000).

    Article  CAS  Google Scholar 

  5. Thannickal, T.C. et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474 (2000).

    Article  CAS  Google Scholar 

  6. Cvetkovic-Lopes, V. et al. Elevated Tribbles homolog 2 specific antibody levels in narcolepsy patients. J. Clin. Invest. 120, 713–719 (2010).

    Article  CAS  Google Scholar 

  7. Miyagawa, T. et al. Variant between CPT1B and CHKB associated with susceptibility to narcolepsy. Nat. Genet. 40, 1324–1328 (2008).

    Article  CAS  Google Scholar 

  8. Hallmayer, J. et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat. Genet. 41, 708–711 (2009).

    Article  CAS  Google Scholar 

  9. Lettre, G. & Rioux, J.D. Autoimmune diseases: insights from genome-wide association studies. Hum. Mol. Genet. 17, R116–R121 (2008).

    Article  CAS  Google Scholar 

  10. Klein, J. & Sato, A. The HLA system. Second of two parts. N. Engl. J. Med. 343, 782–786 (2000).

    Article  CAS  Google Scholar 

  11. Korbel, J.O. et al. Systematic prediction and validation of breakpoints associated with copy-number variants in the human genome. Proc. Natl. Acad. Sci. USA 104, 10110–10115 (2007).

    Article  CAS  Google Scholar 

  12. McCarroll, S.A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat. Genet. 40, 1166–1174 (2008).

    Article  CAS  Google Scholar 

  13. Perry, G.H. et al. Copy number variation and evolution in humans and chimpanzees. Genome Res. 18, 1698–1710 (2008).

    Article  CAS  Google Scholar 

  14. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    Article  CAS  Google Scholar 

  15. Wheeler, D.A. et al. The complete genome of an individual by massively parallel DNA sequencing. Nature 452, 872–876 (2008).

    Article  CAS  Google Scholar 

  16. Wong, K.K. et al. A comprehensive analysis of common copy-number variations in the human genome. Am. J. Hum. Genet. 80, 91–104 (2007).

    Article  CAS  Google Scholar 

  17. Wellcome Trust Case Control Consortium. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464, 713–720 (2010).

  18. Mignot, E. et al. DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans. Sleep 17, S60–S67 (1994).

    Article  CAS  Google Scholar 

  19. Mignot, E. et al. Extensive HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy. Tissue Antigens 49, 329–341 (1997).

    Article  CAS  Google Scholar 

  20. Firmann, M. et al. The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome. BMC Cardiovasc. Disord. 8, 6 (2008).

    Article  Google Scholar 

  21. Billiard, M. Diagnosis of narcolepsy and idiopathic hypersomnia. An update based on the International classification of sleep disorders, 2nd edition. Sleep Med. Rev. 11, 377–388 (2007).

    Article  Google Scholar 

  22. Weir, B.S., Anderson, A.D. & Hepler, A.B. Genetic relatedness analysis: modern data and new challenges. Nat. Rev. Genet. 7, 771–780 (2006).

    Article  CAS  Google Scholar 

  23. Novembre, J. et al. Genes mirror geography within Europe. Nature 456, 98–101 (2008).

    Article  CAS  Google Scholar 

  24. Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    Article  CAS  Google Scholar 

  25. Benjamini, Y., Drai, D., Elmer, G., Kafkafi, N. & Golani, I. Controlling the false discovery rate in behavior genetics research. Behav. Brain Res. 125, 279–284 (2001).

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations



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.

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Correspondence to Mehdi Tafti.

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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.

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Hor, H., Kutalik, Z., Dauvilliers, Y. et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genet 42, 786–789 (2010).

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