Common variants in P2RY11 are associated with narcolepsy

• DOI: 10.1038/ng.734
• Publication Date: 2010-12-19T19:13:16Z
• Authors: Birgitte R Kornum; Minae Kawashima; Juliette Faraco; Ling Lin; Thomas J Rico; Stephanie Hesselson; Robert C Axtell; Hedwich Kuipers; Karin Weiner; Alexandra Hamacher; Matthias U Kassack; Fang Han; Stine Knudsen; Jing Li; Xiaosong Dong; Juliane Winkelmann; Giuseppe Plazzi; Sona Nevsimalova; Seung-Chul Hong; Yutaka Honda; Makoto Honda; Birgit Högl; Thanh G N Ton; Jacques Montplaisir; Patrice Bourgin; David Kemlink; Yu-Shu Huang; Simon Warby; Mali Einen; Jasmin L Eshragh; Taku Miyagawa; Alex Desautels; Elisabeth Ruppert; Per Egil Hesla; Francesca Poli; Fabio Pizza; Birgit Frauscher; Jong-Hyun Jeong; Sung-Pil Lee; Kingman P Strohl; William T Longstreth; Mark Kvale; Marie Dobrovolna; Maurice M Ohayon; Gerald T Nepom; H-Erich Wichmann; Guy A Rouleau; Christian Gieger; Douglas F Levinson; Pablo V Gejman; Thomas Meitinger; Paul Peppard; Terry Young; Poul Jennum; Lawrence Steinman; Katsushi Tokunaga; Pui-Yan Kwok; Neil Risch; Joachim Hallmayer; Emmanuel Mignot
• Keywords: Asian Continental Ancestry Group; 0301 basic medicine; Ethnic Groups/genetics; European Continental Ancestry Group; Medical and Health Sciences; P2RY11; narcolepsy; narcolepsy with cataplexy; genome-wide association; Polymorphism, Single Nucleotide; Article; White People; 03 medical and health sciences; Asian People; Receptors; Genetics; Ethnicity; Odds Ratio; 2.1 Biological and endogenous factors; Humans; Genetic Predisposition to Disease; Polymorphism; Aetiology; Alleles; Purinergic P2/genetics; Narcolepsy; African Americans; Purinergic P2; Whites; Receptors, Purinergic P2; Narcolepsy/genetics; Human Genome; Genetic Variation; Single Nucleotide; Biological Sciences; Brain Disorders; 3. Good health; Asians; Black or African American; Case-Control Studies; Developmental Biology; Genome-Wide Association Study

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.