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.
Hallmayer
Joachim
J
Center for Sleep Sciences, Stanford University School of Medicine, Palo Alto, California, USA.
Faraco
Juliette
J
Lin
Ling
L
Hesselson
Stephanie
S
Winkelmann
Juliane
J
Kawashima
Minae
M
Mayer
Geert
G
Plazzi
Giuseppe
G
Nevsimalova
Sona
S
Bourgin
Patrice
P
Hong
Seung-Chul
SC
Hong
Sheng Seung-Chul
SS
Honda
Yutaka
Y
Honda
Makoto
M
Högl
Birgit
B
Longstreth
William T
WT
Montplaisir
Jacques
J
Kemlink
David
D
Einen
Mali
M
Chen
Justin
J
Musone
Stacy L
SL
Akana
Matthew
M
Miyagawa
Taku
T
Duan
Jubao
J
Desautels
Alex
A
Erhardt
Christine
C
Hesla
Per Egil
PE
Poli
Francesca
F
Frauscher
Birgit
B
Jeong
Jong-Hyun
JH
Lee
Sung-Pil
SP
Ton
Thanh G N
TG
Kvale
Mark
M
Kolesar
Libor
L
Dobrovolná
Marie
M
Nepom
Gerald T
GT
Salomon
Dan
D
Wichmann
H-Erich
HE
Rouleau
Guy A
GA
Gieger
Christian
C
Levinson
Douglas F
DF
Gejman
Pablo V
PV
Meitinger
Thomas
T
Young
Terry
T
Peppard
Paul
P
Tokunaga
Katsushi
K
Kwok
Pui-Yan
PY
Risch
Neil
N
Mignot
Emmanuel
E
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