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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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.
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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.
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Kornum, B., Kawashima, M., Faraco, J. et al. Common variants in P2RY11 are associated with narcolepsy. Nat Genet 43, 66–71 (2011). https://doi.org/10.1038/ng.734
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DOI: https://doi.org/10.1038/ng.734
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