Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects.
Retrospective case-control study.
A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication.
PATIENTS AND PARTICIPANTS:
For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included.
MEASUREMENTS AND RESULTS:
None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2×10(-9)) and rs1154155 within the TRA locus (P < 2×10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified.
An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.
Tafti M; Hor H; Dauvilliers Y; Lammers GJ; Overeem S; Mayer G; Javidi S; Iranzo A; Santamaria J; Peraita-Adrados R; Vicario JL; Arnulf I; Plazzi G; Bayard S; Poli F; Pizza F; Geisler P; Wierzbicka A; Bassetti CL; Mathis J; Lecendreux M; Donjacour CE; van der Heide A; Heinzer R; Haba-Rubio J; Feketeova E; Högl B; Frauscher B; Benetó A; Khatami R; Cañellas F; Pfister C; Scholz S; Billiard M; Baumann CR; Ercilla G; Verduijn W; Claas FH; Dubois V; Nowak J; Eberhard HP; Pradervand S; Hor CN; Testi M; Tiercy JM; Kutalik Z; on Behalf of the European Narcolepsy Network (EU-NN). DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. SLEEP 2014;37(1):19-25.
Autoimmunity, GWAS, H1N1 vaccination, genetics