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- Title
Narcolepsy is strongly associated with the T-cell receptor alpha locus.
- Authors
Hallmayer, Joachim; Faraco, Juliette; Lin, Ling; Hesselson, Stephanie; Winkelmann, Juliane; Kawashima, Minae; Mayer, Geert; Plazzi, Giuseppe; Nevsimalova, Sona; Bourgin, Patrice; Hong, Seung-Chul; Honda, Yutaka; Honda, Makoto; Högl, Birgit; Longstreth, William T, Jr; Montplaisir, Jacques; Kemlink, David; Einen, Mali; Chen, Justin; Musone, Stacy L; Akana, Matthew; Miyagawa, Taku; Duan, Jubao; Desautels, Alex; Erhardt, Christine; Hesla, Per Egil; Poli, Francesca; Frauscher, Birgit; Jeong, Jong-Hyun; Lee, Sung-Pil; Ton, Thanh G N; Kvale, Mark; Kolesar, Libor; Dobrovolná, Marie; Nepom, Gerald T; Salomon, Dan; Wichmann, H-Erich; Rouleau, Guy A; Gieger, Christian; Levinson, Douglas F; Gejman, Pablo V; Meitinger, Thomas; Young, Terry; Peppard, Paul; Tokunaga, Katsushi; Kwok, Pui-Yan; Risch, Neil; Mignot, Emmanuel
- 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.
- Publication
Nature genetics, 2009, Vol 41, Issue 6, p708
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.372