Abstract
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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Acknowledgements
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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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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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). https://doi.org/10.1038/ng.647
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DOI: https://doi.org/10.1038/ng.647
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