Common variants in P2RY11 are associated with narcolepsy

被引：172

作者：

Kornum, Birgitte R. ^{[1
,2
,3
]}

Kawashima, Minae ^{[1
,2
,4
]}

Faraco, Juliette ^{[1
,2
]}

Lin, Ling ^{[1
,2
]}

Rico, Thomas J. ^{[1
,2
]}

Hesselson, Stephanie ^{[5
]}

Axtell, Robert C. ^{[6
]}

Kuipers, Hedwich ^{[6
]}

Weiner, Karin ^{[1
,2
]}

Hamacher, Alexandra ^{[7
]}

Kassack, Matthias U. ^{[7
]}

Han, Fang ^{[8
]}

Knudsen, Stine ^{[3
]}

Li, Jing ^{[8
]}

Dong, Xiaosong ^{[8
]}

Winkelmann, Juliane ^{[9
,10
,11
]}

Plazzi, Giuseppe ^{[12
]}

Nevsimalova, Sona ^{[13
,14
]}

Hong, Seung-Chul ^{[15
]}

Honda, Yutaka ^{[16
]}

Honda, Makoto ^{[17
]}

Hogl, Birgit ^{[18
]}

Ton, Thanh G. N. ^{[19
,20
]}

Montplaisir, Jacques ^{[21
]}

Bourgin, Patrice ^{[22
]}

Kemlink, David ^{[13
,14
]}

Huang, Yu-Shu ^{[23
,24
]}

Warby, Simon ^{[1
,2
]}

Einen, Mali ^{[1
,2
]}

Eshragh, Jasmin L. ^{[5
]}

Miyagawa, Taku ^{[4
]}

Desautels, Alex ^{[21
]}

Ruppert, Elisabeth ^{[22
]}

Hesla, Per Egil ^{[25
]}

Poli, Francesca ^{[12
]}

Pizza, Fabio ^{[12
]}

Frauscher, Birgit ^{[18
]}

Jeong, Jong-Hyun ^{[15
]}

Lee, Sung-Pil ^{[15
]}

Strohl, Kingman P. ^{[26
]}

Longstreth, William T., Jr. ^{[19
,20
]}

Kvale, Mark ^{[5
]}

Dobrovolna, Marie ^{[27
]}

Ohayon, Maurice M. ^{[1
,2
]}

Nepom, Gerald T. ^{[28
]}

Wichmann, H-Erich ^{[29
,30
]}

Rouleau, Guy A. ^{[31
,32
]}

Gieger, Christian ^{[30
]}

Levinson, Douglas F. ^{[1
,2
]}

Gejman, Pablo V. ^{[33
]}

机构：

[1] Stanford Univ, Sch Med, Ctr Sleep Sci, Palo Alto, CA 94304 USA

[2] Stanford Univ, Sch Med, Dept Psychiat, Palo Alto, CA 94304 USA

[3] Univ Copenhagen, Glostrup Hosp, Danish Ctr Sleep Med, Glostrup, Denmark

[4] Univ Tokyo, Dept Human Genet, Tokyo, Japan

[5] Univ Calif San Francisco, Sch Med, Inst Human Genet, San Francisco, CA USA

[6] Stanford Univ, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA

[7] Univ Dusseldorf, Inst Pharmaceut & Med Chem, Dusseldorf, Germany

[8] Beijing Univ, Peoples Hosp, Dept Pulm Med, Beijing 100871, Peoples R China

[9] Tech Univ Munich, Inst Human Genet, Munich, Germany

[10] Tech Univ Munich, Dept Neurol, Munich, Germany

[11] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[12] Univ Bologna, Dept Neurol Sci, Bologna, Italy

[13] Charles Univ Prague, Fac Med 1, Dept Neurol, Prague, Czech Republic

[14] Gen Univ Hosp, Prague, Czech Republic

[15] Catholic Univ Korea, St Vincents Hosp, Dept Neuropsychiat, Suwon, South Korea

[16] Japan Sornnol Ctr, Neuropsychiat Res Inst, Tokyo, Japan

[17] Tokyo Metropolitan Org Med Res, Tokyo Inst Psychiat, Tokyo, Japan

[18] Innsbruck Med Univ, Dept Neurol, Innsbruck, Austria

[19] Univ Washington, Dept Neurol, Seattle, WA 98195 USA

[20] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[21] Univ Montreal, Sleep Disorders Ctr, Montreal, PQ, Canada

[22] Univ Strasbourg, Hop Civil, Sleep Clin, Strasbourg, France

[23] Chang Gung Mem Univ Hosp, Dept Child Psychiat, Taipei, Taiwan

[24] Chang Gung Mem Univ Hosp, Dept Sleep Med, Taipei, Taiwan

[25] Coliseum Majorstua Clin, Med Sect, Electroencephalog EEG Lab, Oslo, Norway

[26] Vet Adm Med Ctr, Div Pulm & Crit Care Med, Cleveland, OH 44106 USA

[27] Inst Hematol & Blood Transfus, Natl Reference Lab DNA Diagnost, HLA Typing Lab, CR-12820 Prague, Czech Republic

[28] Benaroya Res Inst Virginia Mason, Seattle, WA USA

[29] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Munich, Germany

[30] Univ Munich, Inst Med Informat Biometry & Epidemiol, D-80539 Munich, Germany

[31] Ctr Hosp Univ Montreal, Ctr Rech, Ctr Excellence Neurom, Montreal, PQ, Canada

[32] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada

[33] Evanston NW Healthcare Res Inst, Dept Psychiat & Behav Sci, Evanston, IL USA

[34] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI USA

[35] Kaiser Permanente No Calif Div Res, Oakland, CA USA

[36] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 01期

基金：

美国国家卫生研究院;

关键词：

P2Y(11) RECEPTOR; ENDOTHELIAL-CELLS; DENDRITIC CELLS; T-LYMPHOCYTES; ATP; ACTIVATION; ONSET; AUTOANTIBODIES; SUSCEPTIBILITY; INFLAMMATION;

D O I：

10.1038/ng.734

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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(11) gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 x 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.

引用

页码：66 / U90

页数：7

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