Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy.
Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.
Hor
Hyun
H
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Kutalik
Zoltán
Z
Dauvilliers
Yves
Y
Valsesia
Armand
A
Lammers
Gert J
GJ
Donjacour
Claire E H M
CE
Iranzo
Alex
A
Santamaria
Joan
J
Peraita Adrados
Rosa
R
Vicario
José L
JL
Overeem
Sebastiaan
S
Arnulf
Isabelle
I
Theodorou
Ioannis
I
Jennum
Poul
P
Knudsen
Stine
S
Bassetti
Claudio
C
Mathis
Johannes
J
Lecendreux
Michel
M
Mayer
Geert
G
Geisler
Peter
P
Benetó
Antonio
A
Petit
Brice
B
Pfister
Corinne
C
Bürki
Julie Vienne
JV
Didelot
Gérard
G
Billiard
Michel
M
Ercilla
Guadalupe
G
Verduijn
Willem
W
Claas
Frans H J
FH
Vollenweider
Peter
P
Vollenwider
Peter
P
Waeber
Gerard
G
Waterworth
Dawn M
DM
Mooser
Vincent
V
Heinzer
Raphaël
R
Beckmann
Jacques S
JS
Bergmann
Sven
S
Tafti
Mehdi
M
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006681:HLA-D Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy / Q000235:genetics*; D044465:White People / Q000235:genetics
D006681:HLA-D Antigens