Common variants in P2RY11 are associated with narcolepsy

Research output: Contribution to journalJournal articleResearchpeer-review

  • 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

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.

Original languageEnglish
JournalNature Genetics
Issue number1
Pages (from-to)66-71
Number of pages6
Publication statusPublished - Jan 2011

    Research areas

  • African Americans, Alleles, Asian Continental Ancestry Group, Case-Control Studies, Ethnic Groups/genetics, European Continental Ancestry Group, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Narcolepsy/genetics, Odds Ratio, Polymorphism, Single Nucleotide, Receptors, Purinergic P2/genetics

ID: 196168888