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 × 10−8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 × 10−43) and DRB1*1301-DQB1*0603 (P < 3 × 10−7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 × 10−14). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.
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We thank all the subjects for their generous participation in this study; our colleagues K. Harshman and O. Hagenbuchle and the staff of the Lausanne DNA array facility for their expert technical assistance; and F. Canellas from the University Hospital Son Dureta, Palma-Spain and P. Young from the Department of Neurology, University Hospital Muenster-Germany for providing additional data on narcolepsy patients. Support for this research was provided by the French Ministry of Research and Higher Education, Project Agence Nationale de la Recherche-07-MRAR (France), PHRC 2007-P070138 (France), European Narcolepsy Network, an unrestricted grant from UCB Pharma S.A. (Belgium), the University and the State of Vaud (Switzerland), the Swiss National Science Foundation (grants 3100AO-108478/2, 3100AO-116323/1 and 310000-112552/1), the European Framework Project 6 (EuroDia and the AnEuploidy projects) and GlaxoSmithKline (which sponsored in part the CoLaus study). S.B. is funded by the Giorgi-Cavaglieri Foundation and the Leenaards Foundation. Special thanks to T. Johnson for his valuable advice on data analysis. The computations were performed in part at the Vital-IT center for high-performance computing of the Swiss Institute of Bioinformatics. This study was conducted on behalf of the European Narcolepsy Network.
Supplementary Note, Supplementary Tables 1–3 and Supplementary Figures 1 and 2
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Molecular Psychiatry (2019)