• An Erratum to this article was published on 28 September 2011

This article has been updated

Abstract

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10−10, odds ratio = 1.28, 95% CI 1.19–1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8+ T lymphocytes (72% reduced, P = 0.003) and natural killer (NK) cells (70% reduced, P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.

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Change history

  • 22 September 2011

    In the version of this article initially published, the percentage reduction of P2RY11 expression in CD8+ T lymphocytes was incorrectly given as 339%, when it should have been 72%. The percentage was not given for NK cells and should have been 70%. The errors have been corrected in the HTML and PDF versions of the article.

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References

  1. 1.

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

  2. 2.

    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).

  3. 3.

    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).

  4. 4.

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

  5. 5.

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

  6. 6.

    et al. Anti-Tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy. Sleep 33, 869–874 (2010).

  7. 7.

    et al. Anti-Tribbles homolog 2 autoantibodies in Japanese patients with narcolepsy. Sleep 33, 875–878 (2010).

  8. 8.

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

  9. 9.

    et al. DQB1*0301 and DQB1*0601 modulate narcolepsy susceptibility in Koreans. Hum. Immunol. 68, 59–68 (2007).

  10. 10.

    et al. Increased risk of acute myocardial infarction and elevated levels of C-reactive protein in carriers of the Thr-87 variant of the ATP receptor P2Y11. Eur. Heart J. 28, 13–18 (2007).

  11. 11.

    et al. DQ (rather than DR) gene marks susceptibility to narcolepsy. Lancet 339, 1052 (1992).

  12. 12.

    , , , & Cotranscription and intergenic splicing of human P2Y11 and SSF1 genes. J. Biol. Chem. 276, 16561–16566 (2001).

  13. 13.

    , , , & Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol. Ther. 112, 358–404 (2006).

  14. 14.

    , & Extracellular nucleotides as negative modulators of immunity. Curr. Opin. Pharmacol. 9, 507–513 (2009).

  15. 15.

    , , & Cloning of a human purinergic P2Y receptor coupled to phospholipase C and adenylyl cyclase. J. Biol. Chem. 272, 31969–31973 (1997).

  16. 16.

    & Increased release of ATP from endothelial cells during acute inflammation. Inflamm. Res. 47, 351–354 (1998).

  17. 17.

    et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314, 1792–1795 (2006).

  18. 18.

    et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009).

  19. 19.

    , , & Concomitant activation of P2Y(2) and P2Y(6) receptors on monocytes is required for TLR1/2-induced neutrophil migration by regulating IL-8 secretion. Eur. J. Immunol. 39, 2885–2894 (2009).

  20. 20.

    , & P2Z purinoceptor, a special receptor for apoptosis induced by ATP in human leukemic lymphocytes. Chin. Med. J. 112, 356–362 (1999).

  21. 21.

    , & High sensitivity of CD4+CD25+ regulatory T cells to extracellular metabolites nicotinamide adenine dinucleotide and ATP: a role for P2X7 receptors. J. Immunol. 175, 3075–3083 (2005).

  22. 22.

    & P2X7 receptor expression levels determine lethal effects of a purine based danger signal in T lymphocytes. Cell. Immunol. 243, 58–65 (2006).

  23. 23.

    et al. Sequential shrinkage and swelling underlie P2X7-stimulated lymphocyte phosphatidylserine exposure and death. J. Immunol. 180, 300–308 (2008).

  24. 24.

    et al. Expression pattern of human P2Y receptor subtypes: a quantitative reverse transcription-polymerase chain reaction study. Biochim. Biophys. Acta 1521, 107–119 (2001).

  25. 25.

    et al. Inhibition of neutrophil apoptosis by ATP is mediated by the P2Y11 receptor. J. Immunol. 179, 8544–8553 (2007).

  26. 26.

    et al. ATP gradients inhibit the migratory capacity of specific human dendritic cell types: implications for P2Y11 receptor signaling. Blood 102, 613–620 (2003).

  27. 27.

    et al. Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency. J. Med. Chem. 48, 7040–7048 (2005).

  28. 28.

    et al. NF546 [4,4′-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1 (4-methyl-phenylene)-carbonylimino))-bis(1,3-xylene-alpha,alpha′-diphosphonic acid) tetrasodium salt] is a non-nucleotide P2Y11 agonist and stimulates release of IL-8 from human monocyte-derived dendritic cells. J. Pharmacol. Exp. Ther. 332, 238–247 (2010).

  29. 29.

    et al. Extracellular adenine nucleotides inhibit the activation of human CD4+ T lymphocytes. J. Immunol. 169, 15–21 (2002).

  30. 30.

    et al. ATP secreted by endothelial cells blocks CX3CL1-elicited natural killer cell chemotaxis and cytotoxicity via P2Y11 receptor activation. Blood 116, 4492–4500 (2010).

  31. 31.

    et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 32, 979–983 (2009).

  32. 32.

    et al. Involvement of multiple P2Y receptors and signaling pathways in the action of adenine nucleotides diphosphates on human monocyte-derived dendritic cells. J. Leukoc. Biol. 76, 796–803 (2004).

  33. 33.

    et al. The P2Y11 receptor mediates the ATP-induced maturation of human monocyte-derived dendritic cells. J. Immunol. 166, 7172–7177 (2001).

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Acknowledgements

We are indebted to all the participants of the study, most notably the individuals with narcolepsy. Without their contributions, this study would not have been possible. This study was supported by National Institutes of neurological Disease and Stroke grant P50 NS2372. Additional funding was from the Danish Medical Council 09-066348/FSS to B.R.K., a Stanford training grant: Molecular and Cellular Immunobiology grant 5 T32 AI07290 to K.W., National Institutes of Mental Health grant R01 MH080957 to E.M., grant 5U01 MH079470 to D.L., and US National Institutes of Health NS-044199 to M.M.O. We are also grateful to GAIN (the Genetic Association Information Network, National Institutes of Health) and KORA (Kooperative Gesundheitsforschung in der Region Augsburg, Germany). The authors extend their thanks to P. Chang, A. Voros and J. Zhang for technical assistance and C. Grumet for brainstorming and constant support.

Author information

Affiliations

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

    • Birgitte R Kornum
    • , Minae Kawashima
    • , Juliette Faraco
    • , Ling Lin
    • , Thomas J Rico
    • , Karin Weiner
    • , Simon Warby
    • , Mali Einen
    • , Maurice M Ohayon
    • , Douglas F Levinson
    • , Joachim Hallmayer
    •  & Emmanuel Mignot
  2. Danish Center for Sleep Medicine, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark.

    • Birgitte R Kornum
    • , Stine Knudsen
    •  & Poul Jennum
  3. Department of Human Genetics, University of Tokyo, Tokyo, Japan.

    • Minae Kawashima
    • , Taku Miyagawa
    •  & Katsushi Tokunaga
  4. Institute for Human Genetics, University of California San Francisco School of Medicine, San Francisco, California, USA.

    • Stephanie Hesselson
    • , Jasmin L Eshragh
    • , Mark Kvale
    • , Pui-Yan Kwok
    •  & Neil Risch
  5. Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.

    • Robert C Axtell
    • , Hedwich Kuipers
    •  & Lawrence Steinman
  6. Institute of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Biochemistry, Heinrich-Heine-University of Düsseldorf, Düsseldorf, Germany.

    • Alexandra Hamacher
    •  & Matthias U Kassack
  7. Department of Pulmonary Medicine, The People's Hospital, Beijing University, Beijing, China.

    • Fang Han
    • , Jing Li
    •  & Xiaosong Dong
  8. Institute for Human Genetics, Technische Universität München, Munich, Germany.

    • Juliane Winkelmann
    •  & Thomas Meitinger
  9. Department of Neurology, Technische Universität München, Munich, Germany.

    • Juliane Winkelmann
    •  & Thomas Meitinger
  10. Institute of Human Genetics, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany.

    • Juliane Winkelmann
    •  & Thomas Meitinger
  11. Department of Neurological Sciences, University of Bologna, Bologna, Italy.

    • Giuseppe Plazzi
    • , Francesca Poli
    •  & Fabio Pizza
  12. Department of Neurology, 1st Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic.

    • Sona Nevsimalova
    •  & David Kemlink
  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. Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan.

    • Yutaka Honda
  15. Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan.

    • Makoto Honda
  16. Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.

    • Birgit Högl
    •  & Birgit Frauscher
  17. Department of Neurology, University of Washington, Seattle, Washington, USA.

    • Thanh G N Ton
    •  & William T Longstreth Jr
  18. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Thanh G N Ton
    •  & William T Longstreth Jr
  19. Sleep Disorders Center, Université de Montréal, Montréal, Québec, Canada.

    • Jacques Montplaisir
    •  & Alex Desautels
  20. Sleep Clinic, Hôpital Civil, Louis Pasteur University, Strasbourg, France.

    • Patrice Bourgin
    •  & Elisabeth Ruppert
  21. Department of Child Psychiatry, Chang Gung Memorial University Hospital, Taipei, Taiwan.

    • Yu-Shu Huang
  22. Department of Sleep Medicine, Chang Gung Memorial University Hospital, Taipei, Taiwan.

    • Yu-Shu Huang
  23. Electroencephalography (EEG) Laboratory, Medical Section, Coliseum on Majorstua Clinic, Oslo, Norway.

    • Per Egil Hesla
  24. Division of Pulmonary and Critical Care Medicine, Veterans Administation Medical Center, Cleveland, Ohio, USA.

    • Kingman P Strohl
  25. HLA Typing Lab, National Reference Laboratory for DNA Diagnostics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.

    • Marie Dobrovolna
  26. The Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.

    • Gerald T Nepom
  27. Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Munich, Germany.

    • H-Erich Wichmann
  28. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians—Universität, Munich, Germany.

    • H-Erich Wichmann
    •  & Christian Gieger
  29. Center of Excellence in Neuromics, Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada.

    • Guy A Rouleau
  30. Department of Medicine, Université de Montréal, Montréal, Québec, Canada.

    • Guy A Rouleau
  31. Department of Psychiatry and Behavioral Sciences, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois, USA.

    • Pablo V Gejman
  32. Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

    • Paul Peppard
    •  & Terry Young
  33. Kaiser Permanente Northern California Division of Research, Oakland, California, USA.

    • Neil Risch
  34. Department of Epidemiology and Biostatistics, University of California San Francisco School of Medicine, San Francisco, California, USA.

    • Neil Risch

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Contributions

E.M., B.R.K., J.H. and N.R. designed the study with valuable input from R.C.A., H.K., L.S., K.T. and P.Y.K. B.R.K., M. Kawashima, L.L., S.H., R.C.A., H.K., K.W., J.L.E. and T. Miyagawa generated molecular data. A.H. and M.U.K. provided the P2RY11 agonist and antagonist. B.R.K., J.F., J.H., E.M. and N.R. participated in the data analysis. B.R.K. and E.M. wrote the manuscript. J.F., S.W., M. Kvale, D.F.L., N.R. and J.H. read and substantially commented on the manuscript. E.M., F.H., S.K., J.L., X.D., G.P., S.N., S.C.H., Y.H., M.H., B.H., J.M., P.B., D.K., Y.S.H., M.E., A.D., E.R., P.E.H., F. Poli, F. Pizza, B.F., J.H.J., S.-P.L., K.P.S., W.T.L., M.M.O. and P.J. contributed narcolepsy samples. T.J.R., J.W., T.G.N.T., M.D., G.T.N., H.-E.W., G.A.R., C.G., T. Meitinger, P.P. and T.Y. provided samples and/or genotypes. E.M. provided financial support.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Emmanuel Mignot.

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DOI

https://doi.org/10.1038/ng.734

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