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

Nature Genetics volume 41, pages 708–711 (2009)Cite this article

An Erratum to this article was published on 01 July 2009

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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.

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  • 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.

References

  1. Mignot, E. Genetic and familial aspects of narcolepsy. Neurology 50, S16–S22 (1998).

    Article  CAS  Google Scholar 

  2. Longstreth, W.T. Jr., Koepsell, T.D., Ton, T.G., Hendrickson, A.F. & van Belle, G. The epidemiology of narcolepsy. Sleep 30, 13–26 (2007).

    Article  Google Scholar 

  3. Juji, T., Satake, M., Honda, Y. & Doi, Y. HLA antigens in Japanese patients with narcolepsy. All the patients were DR2 positive. Tissue Antigens 24, 316–319 (1984).

    Article  CAS  Google Scholar 

  4. 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 

  5. Lin, L. et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376 (1999).

    Article  CAS  Google Scholar 

  6. Chemelli, R.M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999).

    Article  CAS  Google Scholar 

  7. 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 

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

    Article  CAS  Google Scholar 

  9. Shiina, T., Inoko, H. & Kulski, J.K. An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens 64, 631–649 (2004).

    Article  CAS  Google Scholar 

  10. Scammell, T.E. The frustrating and mostly fruitless search for an autoimmune cause of narcolepsy. Sleep 29, 601–602 (2006).

    Article  Google Scholar 

  11. Overeem, S., Black, J.L. III & Lammers, G.J. Narcolepsy: immunological aspects. Sleep Med. Rev. 12, 95–107 (2008).

    Article  Google Scholar 

  12. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  13. Seldin, M.F. et al. European population substructure: clustering of northern and southern populations. PLoS Genet. 2, e143 (2006).

    Article  Google Scholar 

  14. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  15. Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

    Article  CAS  Google Scholar 

  16. Ng, M.C. et al. Replication and identification of novel variants at TCF7L2 associated with type 2 diabetes in Hong Kong Chinese. J. Clin. Endocrinol. Metab. 92, 3733–3737 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Garcia, K.C. & Teyton, L. T-cell receptor peptide-MHC interactions: biological lessons from structural studies. Curr. Opin. Biotechnol. 9, 338–343 (1998).

    Article  CAS  Google Scholar 

  19. Haynes, M.R. & Wu, G.E. Evolution of the variable gene segments and recombination signal sequences of the human T-cell receptor alpha/delta locus. Immunogenetics 56, 470–479 (2004).

    Article  CAS  Google Scholar 

  20. Koop, B.F. et al. The human T-cell receptor TCRAC/TCRDC (C alpha/C delta) region: organization, sequence, and evolution of 97.6 kb of DNA. Genomics 19, 478–493 (1994).

    Article  CAS  Google Scholar 

  21. Fuschiotti, P. et al. Analysis of the TCR alpha-chain rearrangement profile in human T lymphocytes. Mol. Immunol. 44, 3380–3388 (2007).

    Article  CAS  Google Scholar 

  22. Lefranc, M.P. et al. IMGT, the international ImMunoGeneTics information system. Nucleic Acids Res. 37, D1006–D1012 (2009).

    Article  CAS  Google Scholar 

  23. Nikolich-Zugich, J., Slifka, M.K. & Messaoudi, I. The many important facets of T-cell repertoire diversity. Nat. Rev. Immunol. 4, 123–132 (2004).

    Article  CAS  Google Scholar 

  24. Sundberg, E.J., Deng, L. & Mariuzza, R.A. TCR recognition of peptide/MHC class II complexes and superantigens. Semin. Immunol. 19, 262–271 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Joachim Hallmayer and Juliette Faraco: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Sleep Sciences, Stanford University School of Medicine, Palo Alto, California, USA

    Joachim Hallmayer, Juliette Faraco, Ling Lin, Minae Kawashima, Mali Einen & Emmanuel Mignot

  2. Department of Psychiatry, Stanford University School of Medicine, Palo Alto, California, USA

    Joachim Hallmayer, Juliette Faraco, Ling Lin, Minae Kawashima, Mali Einen, Douglas F Levinson & Emmanuel Mignot

  3. Institute for Human Genetics, University of California San Francisco School of Medicine, San Francisco, California, USA

    Stephanie Hesselson, Justin Chen, Stacy L Musone, Matthew Akana, Mark Kvale, Pui-Yan Kwok & Neil Risch

  4. Institute for Human Genetics, Technische Universität München, Munich, Germany

    Juliane Winkelmann & Thomas Meitinger

  5. Department of Neurology, Technische Universität München, Munich, Germany

    Juliane Winkelmann

  6. Institute of Human Genetics Helmholtz Zentrum München, Munich, Germany

    Juliane Winkelmann & Thomas Meitinger

  7. Department of Human Genetics, University of Tokyo, Tokyo, Japan

    Minae Kawashima, Taku Miyagawa & Katsushi Tokunaga

  8. Hephata-Klinik, Schwalmstadt-Treysa, Germany

    Geert Mayer

  9. Department of Neurology, Philipps University of Marburg, Marburg, Germany

    Geert Mayer

  10. University of Bologna, Bologna, Italy

    Giuseppe Plazzi & Francesca Poli

  11. Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic

    Sona Nevsimalova & David Kemlink

  12. Sleep Clinic, Hôpital Civil, Louis Pasteur University, Strasbourg, France

    Patrice Bourgin & Christine Erhardt

  13. Department of Neuropsychiatry, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea

    Seung-Chul Hong, Jong-Hyun Jeong & Sung-Pil Lee

  14. Tokyo Institute of Psychiatry, Setagaya, Japan

    Yutaka Honda & Makoto Honda

  15. Department of Neurology, Innsbruck Medical University, Innsbruck, Austria

    Birgit Högl & Birgit Frauscher

  16. Department of Neurology, University of Washington, Seattle, Washington, USA

    William T Longstreth Jr & Thanh G N Ton

  17. Department of Epidemiology, University of Washington, Seattle, Washington, USA

    William T Longstreth Jr & Thanh G N Ton

  18. Sleep Disorders Center, Université de Montréal, Montréal, Québec, Canada

    Jacques Montplaisir & Alex Desautels

  19. Department of Psychiatry, Feinberg School of Medicine, Northwestern University, Evanston, Illinois, USA

    Jubao Duan & Pablo V Gejman

  20. Coliseum on Majorstua Clinic, Oslo, Norway

    Per Egil Hesla

  21. Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Videnska, Prague, Czech Republic

    Libor Kolesar

  22. HLA typing lab, National Reference Laboratory for DNA Diagnostics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic

    Marie Dobrovolná

  23. The Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA

    Gerald T Nepom

  24. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

    Dan Salomon

  25. Institute of Epidemiology Helmholtz Zentrum München, Munich, Germany

    H-Erich Wichmann & Christian Gieger

  26. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany

    H-Erich Wichmann

  27. Center of Excellence in Neuromics, Université de Montréal, Montréal, Canada

    Guy A Rouleau

  28. NorthShore University HealthSystem, Evanston, Illinois, USA

    Pablo V Gejman

  29. Department of Population Health Sciences, University of Wisconsin Medical School, Madison, Wisconsin, USA

    Terry Young & Paul Peppard

  30. Kaiser Permanente Northern California Division of Research, Oakland, California, USA

    Neil Risch

  31. Howard Hughes Medical Institute, Stanford University, California, USA

    Emmanuel Mignot

Authors
  1. Joachim Hallmayer
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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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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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