Narcolepsy is strongly associated with the T-cell receptor alpha locus.
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.
Center for Sleep Sciences, Stanford University School of Medicine, Palo Alto, California, USA.
Joachim
J
Hallmayer
Juliette
J
Faraco
Ling
L
Lin
Stephanie
S
Hesselson
Juliane
J
Winkelmann
Minae
M
Kawashima
Geert
G
Mayer
Giuseppe
G
Plazzi
Sona
S
Nevsimalova
Patrice
P
Bourgin
Seung-Chul
SC
Hong
Sheng Seung-Chul
SS
Hong
Yutaka
Y
Honda
Makoto
M
Honda
Birgit
B
Högl
William T
WT
Longstreth
Jacques
J
Montplaisir
David
D
Kemlink
Mali
M
Einen
Justin
J
Chen
Stacy L
SL
Musone
Matthew
M
Akana
Taku
T
Miyagawa
Jubao
J
Duan
Alex
A
Desautels
Christine
C
Erhardt
Per Egil
PE
Hesla
Francesca
F
Poli
Birgit
B
Frauscher
Jong-Hyun
JH
Jeong
Sung-Pil
SP
Lee
Thanh G N
TG
Ton
Mark
M
Kvale
Libor
L
Kolesar
Marie
M
Dobrovolná
Gerald T
GT
Nepom
Dan
D
Salomon
H-Erich
HE
Wichmann
Guy A
GA
Rouleau
Christian
C
Gieger
Douglas F
DF
Levinson
Pablo V
PV
Gejman
Thomas
T
Meitinger
Terry
T
Young
Paul
P
Peppard
Katsushi
K
Tokunaga
Pui-Yan
PY
Kwok
Neil
N
Risch
Emmanuel
E
Mignot
D000818:Animals; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004285:Dogs; D005838:Genotype; D006801:Humans; D007031:Hypothalamus / Q000276:immunology / Q000473:pathology; D051379:Mice; D009290:Narcolepsy / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*
D016693:Receptors, Antigen, T-Cell, alpha-beta