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 P2Y gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 x 10(1), 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.
Common variants in P2RY11 are associated with narcolepsy
Authors: Kornum BR; Kawashima M; Faraco J; Lin L; Rico TJ; Hesselson S; Axtell RC; Kuipers H; Weiner K; Hamacher A; Kassack MU; Han F; Knudsen S; Li J; Dong X; Winkelmann J; Plazzi G; Nevsimalova S; Hong SC; Honda Y; Honda M; Hogl B; Ton TG; Montplaisir J; Bourgin P; Kemlink D; Huang YS; Warby S; Einen M; Eshragh JL; Miyagawa T; Desautels A; Ruppert E; Hesla PE; Poli F; Pizza F; Frauscher B; Jeong JH; Lee SP; Strohl KP; Longstreth WT; Kvale M; Dobrovolna M; Ohayon MM; Nepom GT; Wichmann HE; Rouleau GA; Gieger C; Levinson DF; Gejman PV; Meitinger T; Peppard P; Young T; Jennum P; Steinman L; Tokunaga K; Kwok PY; Risch N; Hallmayer J; Mignot E
Nat Genet. 2011 Jan;43(1):66-71. Epub 2010 Dec 19.