TY - JOUR

T1 - Common variants in P2RY11 are associated with narcolepsy

AU - Kornum, Birgitte R

AU - Kawashima, Minae

AU - Faraco, Juliette

AU - Lin, Ling

AU - Rico, Thomas J

AU - Hesselson, Stephanie

AU - Axtell, Robert C

AU - Kuipers, Hedwich

AU - Weiner, Karin

AU - Hamacher, Alexandra

AU - Kassack, Matthias U

AU - Han, Fang

AU - Knudsen, Stine

AU - Li, Jing

AU - Dong, Xiaosong

AU - Winkelmann, Juliane

AU - Plazzi, Giuseppe

AU - Nevsimalova, Sona

AU - Hong, Seung-Chul

AU - Honda, Yutaka

AU - Honda, Makoto

AU - Högl, Birgit

AU - Ton, Thanh G N

AU - Montplaisir, Jacques

AU - Bourgin, Patrice

AU - Kemlink, David

AU - Huang, Yu-Shu

AU - Warby, Simon

AU - Einen, Mali

AU - Eshragh, Jasmin L

AU - Miyagawa, Taku

AU - Desautels, Alex

AU - Ruppert, Elisabeth

AU - Hesla, Per Egil

AU - Poli, Francesca

AU - Pizza, Fabio

AU - Frauscher, Birgit

AU - Jeong, Jong-Hyun

AU - Lee, Sung-Pil

AU - Strohl, Kingman P

AU - Longstreth, William T

AU - Kvale, Mark

AU - Dobrovolna, Marie

AU - Ohayon, Maurice M

AU - Nepom, Gerald T

AU - Wichmann, H-Erich

AU - Rouleau, Guy A

AU - Gieger, Christian

AU - Levinson, Douglas F

AU - Jennum, Poul

PY - 2011/1

Y1 - 2011/1

N2 - 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.

AB - 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.

KW - African Americans

KW - Alleles

KW - Asian Continental Ancestry Group

KW - Case-Control Studies

KW - Ethnic Groups/genetics

KW - European Continental Ancestry Group

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Narcolepsy/genetics

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Receptors, Purinergic P2/genetics

U2 - 10.1038/ng.734

DO - 10.1038/ng.734

M3 - Journal article

C2 - 21170044

VL - 43

SP - 66

EP - 71

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -