title: Common variants in P2RY11 are associated with narcolepsy.
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.
authors.affiliation: Center for Sleep Sciences and Department of Psychiatry, Stanford University School of Medicine, Palo Alto, California, USA.
authors.forename: Birgitte R
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authors.lastname: Kornum
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authors.lastname: Hesselson
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authors.forename: Yu-Shu
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authors.forename: Mali
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authors.lastname: Desautels
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authors.forename: Per Egil
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authors.lastname: Hesla
authors.forename: Francesca
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authors.lastname: Poli
authors.forename: Fabio
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authors.lastname: Pizza
authors.forename: Birgit
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authors.lastname: Frauscher
authors.forename: Jong-Hyun
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authors.lastname: Jeong
authors.forename: Sung-Pil
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authors.lastname: Lee
authors.forename: Kingman P
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authors.lastname: Strohl
authors.forename: William T
authors.initials: WT
authors.lastname: Longstreth
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authors.lastname: Kvale
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authors.lastname: Dobrovolna
authors.forename: Maurice M
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authors.lastname: Ohayon
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Guy A
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authors.lastname: Rouleau
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Douglas F
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authors.initials: PV
authors.lastname: Gejman
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authors.lastname: Meitinger
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authors.lastname: Peppard
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authors.lastname: Young
authors.forename: Poul
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authors.lastname: Jennum
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Neil
authors.initials: N
authors.lastname: Risch
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authors.lastname: Hallmayer
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mesh_terms: D001741:Black or African American; D000483:Alleles; D044466:Asian People; D016022:Case-Control Studies; D005006:Ethnicity / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D009290:Narcolepsy / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D044465:White People
chemical_list: C109734:P2RY11 protein, human; D018048:Receptors, Purinergic P2