Letter abstract
Nature Genetics 41, 708 - 711 (2009)
Published online: 3 May 2009 | Corrected online: 26 June 2009 | doi:10.1038/ng.372
There is an Erratum (July 2009) associated with this Letter.
Narcolepsy is strongly associated with the T-cell receptor alpha locus
Joachim Hallmayer1,2,32, Juliette Faraco1,2,32, Ling Lin1,2, Stephanie Hesselson3, Juliane Winkelmann4,5,6, Minae Kawashima1,2,7, Geert Mayer8,9, Giuseppe Plazzi10, Sona Nevsimalova11, Patrice Bourgin12, Seung-Chul Hong13, Yutaka Honda14, Makoto Honda14, Birgit Högl15, William T Longstreth Jr16,17, Jacques Montplaisir18, David Kemlink11, Mali Einen1,2, Justin Chen3, Stacy L Musone3, Matthew Akana3, Taku Miyagawa7, Jubao Duan19, Alex Desautels18, Christine Erhardt12, Per Egil Hesla20, Francesca Poli10, Birgit Frauscher15, Jong-Hyun Jeong13, Sung-Pil Lee13, Thanh G N Ton16,17, Mark Kvale3, Libor Kolesar21, Marie Dobrovolná22, Gerald T Nepom23, Dan Salomon24, H-Erich Wichmann25,26, Guy A Rouleau27, Christian Gieger25, Douglas F Levinson2, Pablo V Gejman19,28, Thomas Meitinger4,6, Terry Young29, Paul Peppard29, Katsushi Tokunaga7, Pui-Yan Kwok3, Neil Risch3,30 & Emmanuel Mignot1,2,31
Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals1, 2. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs5 and mice6, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported7, 8. 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 disorders9; 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 disorders9.
- Center for Sleep Sciences, Stanford University School of Medicine, Palo Alto, California, USA.
- Department of Psychiatry, Stanford University School of Medicine, Palo Alto, California, USA.
- Institute for Human Genetics, University of California San Francisco School of Medicine, San Francisco, California, USA.
- Institute for Human Genetics, Technische Universität München, Munich, Germany.
- Department of Neurology, Technische Universität München, Munich, Germany.
- Institute of Human Genetics Helmholtz Zentrum München, Munich, Germany.
- Department of Human Genetics, University of Tokyo, Tokyo, Japan.
- Hephata-Klinik, Schwalmstadt-Treysa, Germany.
- Department of Neurology, Philipps University of Marburg, Marburg, Germany.
- University of Bologna, Bologna, Italy.
- Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic.
- Sleep Clinic, Hôpital Civil, Louis Pasteur University, Strasbourg, France.
- Department of Neuropsychiatry, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea.
- Tokyo Institute of Psychiatry, Setagaya, Japan.
- Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
- Department of Neurology, University of Washington, Seattle, Washington, USA.
- Department of Epidemiology, University of Washington, Seattle, Washington, USA.
- Sleep Disorders Center, Université de Montréal, Montréal, Québec, Canada.
- Department of Psychiatry, Feinberg School of Medicine, Northwestern University, Evanston, Illinois, USA.
- Coliseum on Majorstua Clinic, Oslo, Norway.
- Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Videnska, Prague, Czech Republic.
- HLA typing lab, National Reference Laboratory for DNA Diagnostics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
- The Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
- Institute of Epidemiology Helmholtz Zentrum München, Munich, Germany.
- Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
- Center of Excellence in Neuromics, Université de Montréal, Montréal, Canada.
- NorthShore University HealthSystem, Evanston, Illinois, USA.
- Department of Population Health Sciences, University of Wisconsin Medical School, Madison, Wisconsin, USA.
- Kaiser Permanente Northern California Division of Research, Oakland, California, USA.
- Howard Hughes Medical Institute, Stanford University, California, USA.
- These authors contributed equally to this work.
Correspondence to: Emmanuel Mignot1,2,31 e-mail: mignot@stanford.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Narcolepsy and the T-cell receptorNature Genetics News and Views (01 Jun 2009)
Genome-wide tagging for everyoneNature Genetics News and Views (01 Nov 2006)
See all 4 matches for News And ViewsRESEARCH
Variant between CPT1B and CHKB associated with susceptibility to narcolepsyNature Genetics Letter (01 Nov 2008)
A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brainsNature Medicine Article (01 Sep 2000)
See all 10 matches for Research
