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Common variants in P2RY11 are associated with narcolepsy.

  • Author(s): Kornum, Birgitte R;
  • Kawashima, Minae;
  • Faraco, Juliette;
  • Lin, Ling;
  • Rico, Thomas J;
  • Hesselson, Stephanie;
  • Axtell, Robert C;
  • Kuipers, Hedwich;
  • Weiner, Karin;
  • Hamacher, Alexandra;
  • Kassack, Matthias U;
  • Han, Fang;
  • Knudsen, Stine;
  • Li, Jing;
  • Dong, Xiaosong;
  • Winkelmann, Juliane;
  • Plazzi, Giuseppe;
  • Nevsimalova, Sona;
  • Hong, Seung-Chul;
  • Honda, Yutaka;
  • Honda, Makoto;
  • Högl, Birgit;
  • Ton, Thanh GN;
  • Montplaisir, Jacques;
  • Bourgin, Patrice;
  • Kemlink, David;
  • Huang, Yu-Shu;
  • Warby, Simon;
  • Einen, Mali;
  • Eshragh, Jasmin L;
  • Miyagawa, Taku;
  • Desautels, Alex;
  • Ruppert, Elisabeth;
  • Hesla, Per Egil;
  • Poli, Francesca;
  • Pizza, Fabio;
  • Frauscher, Birgit;
  • Jeong, Jong-Hyun;
  • Lee, Sung-Pil;
  • Strohl, Kingman P;
  • Longstreth, William T;
  • Kvale, Mark;
  • Dobrovolna, Marie;
  • Ohayon, Maurice M;
  • Nepom, Gerald T;
  • Wichmann, H-Erich;
  • Rouleau, Guy A;
  • Gieger, Christian;
  • Levinson, Douglas F;
  • Gejman, Pablo V;
  • Meitinger, Thomas;
  • Peppard, Paul;
  • Young, Terry;
  • Jennum, Poul;
  • Steinman, Lawrence;
  • Tokunaga, Katsushi;
  • Kwok, Pui-Yan;
  • Risch, Neil;
  • Hallmayer, Joachim;
  • Mignot, Emmanuel
  • et al.

Published Web Location

https://doi.org/10.1038/ng.734
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 (339% reduced, P = 0.003) and natural killer (NK) cells (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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