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

Mehdi Tafti, Hyun Hor, Yves Dauvilliers, Gert J. Lammers, Sebastiaan Overeem, Geert Mayer, Sirous Javidi, Alex Iranzo, Joan Santamaria, Rosa Peraita-Adrados, José L. Vicario, Isabelle Arnulf, Giuseppe Plazzi, Sophie Bayard, Francesca Poli, Fabio Pizza, Peter Geisler, Aleksandra Wierzbicka, Claudio L. Bassetti, Johannes MathisMichel Lecendreux, Claire E H M Donjacour, Astrid Van Der Heide, Raphaël Heinzer, José Haba-Rubio, Eva Feketeova, Birgit Högl, Birgit Frauscher, Antonio Benetó, Ramin Khatami, Francesca Cañellas, Corinne Pfister, Sabine Scholz, Michel Billiard, Christian R. Baumann, Guadalupe Ercilla, Willem Verduijn, Frans H J Claas, Valérie Dubois, Jacek Nowak, Hans Peter Eberhard, Sylvain Pradervand, Charlotte N. Hor, Manuela Testi, Jean Marie Tiercy, Zoltán Kutalik

Research output: Contribution to journalArticlepeer-review

Abstract

Study Objective: 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. 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 narcolepsy were tested for replication. Patients and Participants: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB106:02-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 DQB106:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB106:03, odds ratio 0.17, DQB105:01, odds ratio 0.56, DQB106:09 odds ratio 0.21, DQB102 odds ratio 0.76) were also identified. Conclusion: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB106:02 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.

Original languageEnglish
Pages (from-to)19-25
Number of pages7
JournalSleep
Volume37
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

Keywords

  • Autoimmunity
  • Genetics
  • GWAS
  • H1N1 vaccination

ASJC Scopus subject areas

  • Physiology (medical)
  • Clinical Neurology

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