Narcolepsy is strongly associated with the T-cell receptor alpha locus

Joachim Hallmayer; Juliette Faraco; Ling Lin; Stephanie Hesselson; Juliane Winkelmann; Minae Kawashima; Geert Mayer; Giuseppe Plazzi; Sona Nevsimalova; Patrice Bourgin; Sheng Seung Chul Hong; Yutaka Honda; Makoto Honda; Birgit Högl; William T. Longstreth; Jacques Montplaisir; David Kemlink; Mali Einen; Justin Chen; Stacy L. Musone; Matthew Akana; Taku Miyagawa; Jubao Duan; Alex Desautels; Christine Erhardt; Per Egil Hesla; Francesca Poli; Birgit Frauscher; Jong Hyun Jeong; Sung Pil Lee; Thanh G.N. Ton; Mark Kvale; Libor Kolesar; Marie Dobrovolná; Gerald T. Nepom; Dan Salomon; H. Erich Wichmann; Guy A. Rouleau; Christian Gieger; Douglas F. Levinson; Pablo V. Gejman; Thomas Meitinger; Terry Young; Paul Peppard; Katsushi Tokunaga; Pui Yan Kwok; Neil Risch; Emmanuel Mignot

doi:10.1038/ng.372

Narcolepsy is strongly associated with the T-cell receptor alpha locus

Joachim Hallmayer, Juliette Faraco, Ling Lin, Stephanie Hesselson, Juliane Winkelmann, Minae Kawashima, Geert Mayer, Giuseppe Plazzi, Sona Nevsimalova, Patrice Bourgin, Sheng Seung Chul Hong, Yutaka Honda, Makoto Honda, Birgit Högl, William T. Longstreth, Jacques Montplaisir, David Kemlink, Mali Einen, Justin Chen, Stacy L. MusoneMatthew Akana, Taku Miyagawa, Jubao Duan, Alex Desautels, Christine Erhardt, Per Egil Hesla, Francesca Poli, Birgit Frauscher, Jong Hyun Jeong, Sung Pil Lee, Thanh G.N. Ton, Mark Kvale, Libor Kolesar, Marie Dobrovolná, Gerald T. Nepom, Dan Salomon, H. Erich Wichmann, Guy A. Rouleau, Christian Gieger, Douglas F. Levinson, Pablo V. Gejman, Thomas Meitinger, Terry Young, Paul Peppard, Katsushi Tokunaga, Pui Yan Kwok, Neil Risch, Emmanuel Mignot

Publikation: Beitrag in Fachzeitschrift › Artikel › Begutachtung

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Abstract

Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1 0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P 10 21, 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.

Originalsprache	Englisch
Seiten (von - bis)	708-711
Seitenumfang	4
Fachzeitschrift	Nature Genetics
Jahrgang	41
Ausgabenummer	6
DOIs	https://doi.org/10.1038/ng.372
Publikationsstatus	Veröffentlicht - Juni 2009

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Hallmayer, J., Faraco, J., Lin, L., Hesselson, S., Winkelmann, J., Kawashima, M., Mayer, G., Plazzi, G., Nevsimalova, S., Bourgin, P., Hong, S. S. C., Honda, Y., Honda, M., Högl, B., Longstreth, W. T., Montplaisir, J., Kemlink, D., Einen, M., Chen, J., ... Mignot, E. (2009). Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nature Genetics, 41(6), 708-711. https://doi.org/10.1038/ng.372

@article{89053f57a976481e9fd40c006fdc1535,

title = "Narcolepsy is strongly associated with the T-cell receptor alpha locus",

abstract = "Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1 0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P 10 21, 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.",

author = "Joachim Hallmayer and Juliette Faraco and Ling Lin and Stephanie Hesselson and Juliane Winkelmann and Minae Kawashima and Geert Mayer and Giuseppe Plazzi and Sona Nevsimalova and Patrice Bourgin and Hong, {Sheng Seung Chul} and Yutaka Honda and Makoto Honda and Birgit H{\"o}gl and Longstreth, {William T.} and Jacques Montplaisir and David Kemlink and Mali Einen and Justin Chen and Musone, {Stacy L.} and Matthew Akana and Taku Miyagawa and Jubao Duan and Alex Desautels and Christine Erhardt and Hesla, {Per Egil} and Francesca Poli and Birgit Frauscher and Jeong, {Jong Hyun} and Lee, {Sung Pil} and Ton, {Thanh G.N.} and Mark Kvale and Libor Kolesar and Marie Dobrovoln{\'a} and Nepom, {Gerald T.} and Dan Salomon and Wichmann, {H. Erich} and Rouleau, {Guy A.} and Christian Gieger and Levinson, {Douglas F.} and Gejman, {Pablo V.} and Thomas Meitinger and Terry Young and Paul Peppard and Katsushi Tokunaga and Kwok, {Pui Yan} and Neil Risch and Emmanuel Mignot",

note = "Funding Information: We are most indebted to all the participants of the study, most notably the subjects with narcolepsy. This study was supported primarily by the US National Institutes of Neurological Disease and Stroke grant P50 NS2372. Additional funding included National Institutes of Mental Health R01 MH080957 to E.M., 5U01 MH079470 to D.F.L., 5U01 MH079469-02 to P.V.G., R01 HL62252 to T.Y. Czech Ministry of Education MSM0021620849 and MZO 0002373601 to S.N., National institutes of Allergic and Infectious diseases 5U19 AI063603 to D.S., National Institute of Neurological Disorders and Stroke R01 NS38523 to W.T.L., MIUR PRIN Grant 2005065029 to G.P. and a grant from Grants-in-Aid for Scientific Research on Comprehensive Genomics from the Ministry of Education, Culture, Sports, Science and Technology of Japan to K.T. G.A.R. is supported by the Canadian Institutes of Health Research. Grant MGC 77493 to J. Montplaisir. E.M. is an HHMI supported investigator. We are also grateful to GAIN (the Genetic Association Information Network, NIH) and KORA (Kooperative Gesundheitsforschung in der Region Augsburg, Germany). The KORA research platform was initiated and financed by the German Federal Ministry of Education and Research and by the State of Bavaria. The authors extend their thanks to E. Wan, C. Chu, C. Ha, J. Zhang and A. Voros for technical assistance, and C. Grumet for brainstorming and constant support.",

year = "2009",

month = jun,

doi = "10.1038/ng.372",

language = "English",

volume = "41",

pages = "708--711",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

Hallmayer, J, Faraco, J, Lin, L, Hesselson, S, Winkelmann, J, Kawashima, M, Mayer, G, Plazzi, G, Nevsimalova, S, Bourgin, P, Hong, SSC, Honda, Y, Honda, M, Högl, B, Longstreth, WT, Montplaisir, J, Kemlink, D, Einen, M, Chen, J, Musone, SL, Akana, M, Miyagawa, T, Duan, J, Desautels, A, Erhardt, C, Hesla, PE, Poli, F, Frauscher, B, Jeong, JH, Lee, SP, Ton, TGN, Kvale, M, Kolesar, L, Dobrovolná, M, Nepom, GT, Salomon, D, Wichmann, HE, Rouleau, GA, Gieger, C, Levinson, DF, Gejman, PV, Meitinger, T, Young, T, Peppard, P, Tokunaga, K, Kwok, PY, Risch, N & Mignot, E 2009, 'Narcolepsy is strongly associated with the T-cell receptor alpha locus', Nature Genetics, Jg. 41, Nr. 6, S. 708-711. https://doi.org/10.1038/ng.372

TY - JOUR

T1 - Narcolepsy is strongly associated with the T-cell receptor alpha locus

AU - Hallmayer, Joachim

AU - Faraco, Juliette

AU - Lin, Ling

AU - Hesselson, Stephanie

AU - Winkelmann, Juliane

AU - Kawashima, Minae

AU - Mayer, Geert

AU - Plazzi, Giuseppe

AU - Nevsimalova, Sona

AU - Bourgin, Patrice

AU - Hong, Sheng Seung Chul

AU - Honda, Yutaka

AU - Honda, Makoto

AU - Högl, Birgit

AU - Longstreth, William T.

AU - Montplaisir, Jacques

AU - Kemlink, David

AU - Einen, Mali

AU - Chen, Justin

AU - Musone, Stacy L.

AU - Akana, Matthew

AU - Miyagawa, Taku

AU - Duan, Jubao

AU - Desautels, Alex

AU - Erhardt, Christine

AU - Hesla, Per Egil

AU - Poli, Francesca

AU - Frauscher, Birgit

AU - Jeong, Jong Hyun

AU - Lee, Sung Pil

AU - Ton, Thanh G.N.

AU - Kvale, Mark

AU - Kolesar, Libor

AU - Dobrovolná, Marie

AU - Nepom, Gerald T.

AU - Salomon, Dan

AU - Wichmann, H. Erich

AU - Rouleau, Guy A.

AU - Gieger, Christian

AU - Levinson, Douglas F.

AU - Gejman, Pablo V.

AU - Meitinger, Thomas

AU - Young, Terry

AU - Peppard, Paul

AU - Tokunaga, Katsushi

AU - Kwok, Pui Yan

AU - Risch, Neil

AU - Mignot, Emmanuel

N1 - Funding Information: We are most indebted to all the participants of the study, most notably the subjects with narcolepsy. This study was supported primarily by the US National Institutes of Neurological Disease and Stroke grant P50 NS2372. Additional funding included National Institutes of Mental Health R01 MH080957 to E.M., 5U01 MH079470 to D.F.L., 5U01 MH079469-02 to P.V.G., R01 HL62252 to T.Y. Czech Ministry of Education MSM0021620849 and MZO 0002373601 to S.N., National institutes of Allergic and Infectious diseases 5U19 AI063603 to D.S., National Institute of Neurological Disorders and Stroke R01 NS38523 to W.T.L., MIUR PRIN Grant 2005065029 to G.P. and a grant from Grants-in-Aid for Scientific Research on Comprehensive Genomics from the Ministry of Education, Culture, Sports, Science and Technology of Japan to K.T. G.A.R. is supported by the Canadian Institutes of Health Research. Grant MGC 77493 to J. Montplaisir. E.M. is an HHMI supported investigator. We are also grateful to GAIN (the Genetic Association Information Network, NIH) and KORA (Kooperative Gesundheitsforschung in der Region Augsburg, Germany). The KORA research platform was initiated and financed by the German Federal Ministry of Education and Research and by the State of Bavaria. The authors extend their thanks to E. Wan, C. Chu, C. Ha, J. Zhang and A. Voros for technical assistance, and C. Grumet for brainstorming and constant support.

PY - 2009/6

Y1 - 2009/6

N2 - Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1 0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P 10 21, 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.

AB - Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1 0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P 10 21, 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.

UR - http://www.scopus.com/inward/record.url?scp=66649111903&partnerID=8YFLogxK

U2 - 10.1038/ng.372

DO - 10.1038/ng.372

M3 - Article

C2 - 19412176

AN - SCOPUS:66649111903

SN - 1061-4036

VL - 41

SP - 708

EP - 711

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Narcolepsy is strongly associated with the T-cell receptor alpha locus

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