Common variants in P2RY11 are associated with narcolepsy

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

doi:10.1038/ng.734

Common variants in P2RY11 are associated with narcolepsy

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

Department of Psychiatry

Research output: Contribution to journal › Article › peer-review

200 Scopus citations

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 3ĝ€2 untranslated region of P2RY11, the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 - 10 '10, odds ratio = 1.28, 95% CI 1.19ĝ€"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 language	English
Pages (from-to)	66-71
Number of pages	6
Journal	Nature Genetics
Volume	43
Issue number	1
DOIs	https://doi.org/10.1038/ng.734
State	Published - Jan 2011

Bibliographical note

Funding Information:
We are indebted to all the participants of the study, most notably the individuals with narcolepsy. Without their contributions, this study would not have been possible. This study was supported by National Institutes of neurological Disease and Stroke grant P50 NS2372. Additional funding was from the Danish Medical Council 09-066348/FSS to B.R.K., a Stanford training grant: Molecular and Cellular Immunobiology grant 5 T32 AI07290 to K.W., National Institutes of Mental Health grant R01 MH080957 to E.M., grant 5U01 MH079470 to D.L., and US National Institutes of Health NS-044199 to M.M.O. We are also grateful to GAIN (the Genetic Association Information Network, National Institutes of Health) and KORA (Kooperative Gesundheitsforschung in der Region Augsburg, Germany). The authors extend their thanks to P. Chang, A. Voros and J. Zhang for technical assistance and C. Grumet for brainstorming and constant support.

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Kornum, B. R., Kawashima, M., Faraco, J., Lin, L., Rico, T. J., Hesselson, S., Axtell, R. C., Kuipers, H., Weiner, K., Hamacher, A., Kassack, M. U., Han, F., Knudsen, S., Li, J., Dong, X., Winkelmann, J., Plazzi, G., Nevsimalova, S., Hong, S. C., ... Mignot, E. (2011). Common variants in P2RY11 are associated with narcolepsy. Nature Genetics, 43(1), 66-71. https://doi.org/10.1038/ng.734

@article{de241d38c86b47978538cbc587cde1f1,

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 3ĝ€2 untranslated region of P2RY11, the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 - 10 '10, odds ratio = 1.28, 95\% CI 1.19ĝ€{"}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.",

author = "Kornum, \{Birgitte R.\} and Minae Kawashima and Juliette Faraco and Ling Lin and Rico, \{Thomas J.\} and Stephanie Hesselson and Axtell, \{Robert C.\} and Hedwich Kuipers and Karin Weiner and Alexandra Hamacher and Kassack, \{Matthias U.\} and Fang Han and Stine Knudsen and Jing Li and Xiaosong Dong and Juliane Winkelmann and Giuseppe Plazzi and Sona Nevsimalova and Hong, \{Seung Chul\} and Yutaka Honda and Makoto Honda and Birgit H{\"o}gl and Ton, \{Thanh G.N.\} and Jacques Montplaisir and Patrice Bourgin and David Kemlink and Huang, \{Yu Shu\} and Simon Warby and Mali Einen and Eshragh, \{Jasmin L.\} and Taku Miyagawa and Alex Desautels and Elisabeth Ruppert and Hesla, \{Per Egil\} and Francesca Poli and Fabio Pizza and Birgit Frauscher and Jeong, \{Jong Hyun\} and Lee, \{Sung Pil\} and Strohl, \{Kingman P.\} and Longstreth, \{William T.\} and Mark Kvale and Marie Dobrovolna and Ohayon, \{Maurice M.\} and Nepom, \{Gerald T.\} and Wichmann, \{H. Erich\} and Rouleau, \{Guy A.\} and Christian Gieger and Levinson, \{Douglas F.\} and Gejman, \{Pablo V.\} and Thomas Meitinger and Paul Peppard and Terry Young and Poul Jennum and Lawrence Steinman and Katsushi Tokunaga and Kwok, \{Pui Yan\} and Neil Risch and Joachim Hallmayer and Emmanuel Mignot",

note = "Funding Information: We are indebted to all the participants of the study, most notably the individuals with narcolepsy. Without their contributions, this study would not have been possible. This study was supported by National Institutes of neurological Disease and Stroke grant P50 NS2372. Additional funding was from the Danish Medical Council 09-066348/FSS to B.R.K., a Stanford training grant: Molecular and Cellular Immunobiology grant 5 T32 AI07290 to K.W., National Institutes of Mental Health grant R01 MH080957 to E.M., grant 5U01 MH079470 to D.L., and US National Institutes of Health NS-044199 to M.M.O. We are also grateful to GAIN (the Genetic Association Information Network, National Institutes of Health) and KORA (Kooperative Gesundheitsforschung in der Region Augsburg, Germany). The authors extend their thanks to P. Chang, A. Voros and J. Zhang for technical assistance and C. Grumet for brainstorming and constant support.",

year = "2011",

month = jan,

doi = "10.1038/ng.734",

language = "English",

volume = "43",

pages = "66--71",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "1",

}

Kornum, BR, Kawashima, M, Faraco, J, Lin, L, Rico, TJ, Hesselson, S, Axtell, RC, Kuipers, H, Weiner, K, Hamacher, A, Kassack, MU, Han, F, Knudsen, S, Li, J, Dong, X, Winkelmann, J, Plazzi, G, Nevsimalova, S, Hong, SC, Honda, Y, Honda, M, Högl, B, Ton, TGN, Montplaisir, J, Bourgin, P, Kemlink, D, Huang, YS, Warby, S, Einen, M, Eshragh, JL, Miyagawa, T, Desautels, A, Ruppert, E, Hesla, PE, Poli, F, Pizza, F, Frauscher, B, Jeong, JH, Lee, SP, Strohl, KP, Longstreth, WT, Kvale, M, Dobrovolna, M, Ohayon, MM, Nepom, GT, Wichmann, HE, Rouleau, GA, Gieger, C, Levinson, DF, Gejman, PV, Meitinger, T, Peppard, P, Young, T, Jennum, P, Steinman, L, Tokunaga, K, Kwok, PY, Risch, N, Hallmayer, J & Mignot, E 2011, 'Common variants in P2RY11 are associated with narcolepsy', Nature Genetics, vol. 43, no. 1, pp. 66-71. https://doi.org/10.1038/ng.734

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 - Gejman, Pablo V.

AU - Meitinger, Thomas

AU - Peppard, Paul

AU - Young, Terry

AU - Jennum, Poul

AU - Steinman, Lawrence

AU - Tokunaga, Katsushi

AU - Kwok, Pui Yan

AU - Risch, Neil

AU - Hallmayer, Joachim

AU - Mignot, Emmanuel

N1 - Funding Information: We are indebted to all the participants of the study, most notably the individuals with narcolepsy. Without their contributions, this study would not have been possible. This study was supported by National Institutes of neurological Disease and Stroke grant P50 NS2372. Additional funding was from the Danish Medical Council 09-066348/FSS to B.R.K., a Stanford training grant: Molecular and Cellular Immunobiology grant 5 T32 AI07290 to K.W., National Institutes of Mental Health grant R01 MH080957 to E.M., grant 5U01 MH079470 to D.L., and US National Institutes of Health NS-044199 to M.M.O. We are also grateful to GAIN (the Genetic Association Information Network, National Institutes of Health) and KORA (Kooperative Gesundheitsforschung in der Region Augsburg, Germany). The authors extend their thanks to P. Chang, A. Voros and J. Zhang for technical assistance and C. Grumet for brainstorming and constant support.

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 3ĝ€2 untranslated region of P2RY11, the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 - 10 '10, odds ratio = 1.28, 95% CI 1.19ĝ€"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 3ĝ€2 untranslated region of P2RY11, the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 - 10 '10, odds ratio = 1.28, 95% CI 1.19ĝ€"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.

UR - https://www.scopus.com/pages/publications/78651245467

U2 - 10.1038/ng.734

DO - 10.1038/ng.734

M3 - Article

C2 - 21170044

AN - SCOPUS:78651245467

SN - 1061-4036

VL - 43

SP - 66

EP - 71

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Common variants in P2RY11 are associated with narcolepsy

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