Common variants in P2RY11 are associated with narcolepsy

Kornum B. R.; Kawashima M.; Faraco J.; Lin L.; Rico T. J.; Hesselson S.; Axtell R. C.; Kuipers H.; Weiner K.; Hamacher A.; Kassack M. U.; Han F.; Knudsen S.; Li J.; Dong X.; Winkelmann J.; PLAZZI, GIUSEPPE; Nevsimalova S.; Hong S. C.; Honda Y.; Honda M.; Hogl B.; Ton T. G.; Montplaisir J.; Bourgin P.; Kemlink D.; Huang Y. S.; Warby S.; Einen M.; Eshragh J. L.; Miyagawa T.; Desautels A.; Ruppert E.; Hesla P. E.; POLI, FRANCESCA; PIZZA, FABIO; Frauscher B.; Jeong J. H.; Lee S. P.; Strohl K. P.; Longstreth W. T. J.r.; Kvale M.; Dobrovolna M.; Ohayon M. M.; Nepom G. T.; Wichmann H. E.; Rouleau G. A.; Gieger C.; Levinson D. F.; Gejman P. V.; Meitinger T.; Peppard P.; Young T.; Jennum P.; Steinman L.; Tokunaga K.; Kwok P. Y.; Risch N.; Hallmayer J.; Mognot E.

doi:10.1038/ng.734

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.