DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe

STUDY OBJECTIVE: Prior research has identified five common genetic variants associated with narcolepsywith cataplexyin 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 narcolepsywith cataplexysubjects. DESIGN: Retrospective case-control study. SETTING: 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 narcolepsywere tested for replication. PATIENTS AND PARTICIPANTS: For GWAS, 1,261 narcolepsypatients 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 < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk ( odds ratio251). Four protective alleles (DQB1*06:03, odds ratio0.17, DQB1*05:01, odds ratio0.56, DQB1*06:09 odds ratio0.21, DQB1*02 odds ratio0.76) were also identified. CONCLUSION: An overwhelming portion of genetic risk for narcolepsywith cataplexyis found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsyafter H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.