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- Title
Common variants in P2RY11 are associated with narcolepsy.
- Authors
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 G N; 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, Jr; 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
- 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.
- Publication
Nature genetics, 2011, Vol 43, Issue 1, p66
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.734