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; Poul Jennum

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 HondaMakoto 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, Poul Jennum

Section of General Practice

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
Journal	Nature Genetics
Volume	43
Issue number	1
Pages (from-to)	66-71
Number of pages	6
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.734
Publication status	Published - Jan 2011

Keywords

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

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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., ... Jennum, P. (2011). Common variants in P2RY11 are associated with narcolepsy. Nature Genetics, 43(1), 66-71. https://doi.org/10.1038/ng.734

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, S-C, Honda, Y, Honda, M, Högl, B, Ton, TGN, Montplaisir, J, Bourgin, P, Kemlink, D, Huang, Y-S, Warby, S, Einen, M, Eshragh, JL, Miyagawa, T, Desautels, A, Ruppert, E, Hesla, PE, Poli, F, Pizza, F, Frauscher, B, Jeong, J-H, Lee, S-P, Strohl, KP, Longstreth, WT, Kvale, M, Dobrovolna, M, Ohayon, MM, Nepom, GT, Wichmann, H-E, Rouleau, GA, Gieger, C, Levinson, DF & Jennum, P 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

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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.",

keywords = "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",

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 Seung-Chul Hong 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 Yu-Shu Huang 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 Jong-Hyun Jeong and Sung-Pil Lee and Strohl, {Kingman P} and Longstreth, {William T} and Mark Kvale and Marie Dobrovolna and Ohayon, {Maurice M} and Nepom, {Gerald T} and H-Erich Wichmann and Rouleau, {Guy A} and Christian Gieger and Levinson, {Douglas F} and Poul Jennum",

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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 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.

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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

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

Abstract

Keywords

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