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Narcolepsy is strongly associated with the T-cell receptor alpha locus

An Erratum to this article was published on 01 July 2009

This article has been updated

Abstract

Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals1,2. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs5 and mice6, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported7,8. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10−21, 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders9; thus, narcolepsy will provide new insights on how HLA–TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders9.

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Figure 1: Schematic representation of the TRA@ locus and of SNPs associated with narcolepsy.

Change history

  • 26 June 2009

    NOTE: In the version of this article initially published, Seung-Chul Hong was incorrectly listed as Sheng Seung-Chul Hong. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We are most indebted to all the participants of the study, most notably the subjects with narcolepsy. This study was supported primarily by the US National Institutes of Neurological Disease and Stroke grant P50 NS2372. Additional funding included National Institutes of Mental Health R01 MH080957 to E.M., 5U01 MH079470 to D.F.L., 5U01 MH079469-02 to P.V.G., R01 HL62252 to T.Y. Czech Ministry of Education MSM0021620849 and MZO 0002373601 to S.N., National institutes of Allergic and Infectious diseases 5U19 AI063603 to D.S., National Institute of Neurological Disorders and Stroke R01 NS38523 to W.T.L., MIUR PRIN Grant 2005065029 to G.P. and a grant from Grants-in-Aid for Scientific Research on Comprehensive Genomics from the Ministry of Education, Culture, Sports, Science and Technology of Japan to K.T. G.A.R. is supported by the Canadian Institutes of Health Research. Grant MGC 77493 to J. Montplaisir. E.M. is an HHMI supported investigator. We are also grateful to GAIN (the Genetic Association Information Network, NIH) and KORA (Kooperative Gesundheitsforschung in der Region Augsburg, Germany). The KORA research platform was initiated and financed by the German Federal Ministry of Education and Research and by the State of Bavaria. The authors extend their thanks to E. Wan, C. Chu, C. Ha, J. Zhang and A. Voros for technical assistance, and C. Grumet for brainstorming and constant support.

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Authors and Affiliations

Authors

Contributions

J.H. and J.F. contributed equally to this work. E.M., J.H. and N.R. designed the study. P.-Y.K., L.L., S.H., T.M., J.C., M.A., J.D. and M.K. generated molecular data. J.H., J.F., E.M., N.R., L.L., J.W. and M.K. performed the data analysis. E.M., J.H., J.F. and N.R. wrote the manuscript. E.M., G.M., G.P., S.N., S.H., P.B., Y.H., M.H., B.H., J.M., W.T.L., D.K., M.E., A.D., G.A.R., P.E.H., F.P., B.F., J.-H.J. and S.-P.L. contributed narcolepsy samples. T.G.N.T., L.K., G.T.N., D.S., H.-E.W., G.A.R., C.G., D.F.L., P.V.G., P.P., T.Y., and T.M. provided samples and/or genotypes. E.M. provided financial support.

Corresponding author

Correspondence to Emmanuel Mignot.

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Supplementary Figure 1 and Supplementary Tables 1 and 2 (PDF 337 kb)

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Hallmayer, J., Faraco, J., Lin, L. et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet 41, 708–711 (2009). https://doi.org/10.1038/ng.372

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