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DQB1 Locus Alone Explains Most of the Risk and Protection in Narcolepsy with Cataplexy in Europe

Mehdi Tafti, PhD1,2; Hyun Hor, MD, PhD1,3; Yves Dauvilliers, MD, PhD4,5; Gert J. Lammers, MD, PhD6,7; Sebastiaan Overeem, MD, PhD8; Geert Mayer, MD9; Sirous Javidi, MD9; Alex Iranzo, MD10; Joan Santamaria, MD10; Rosa Peraita-Adrados, MD11; José L. Vicario, PhD12; Isabelle Arnulf, MD, PhD13; Giuseppe Plazzi, MD, PhD14; Sophie Bayard, PhD4,5; Francesca Poli, MD, PhD14; Fabio Pizza, MD, PhD14; Peter Geisler, MD15; Aleksandra Wierzbicka, MD16; Claudio L. Bassetti, MD17; Johannes Mathis, MD17; Michel Lecendreux, MD18; Claire E.H.M. Donjacour, MD6; Astrid van der Heide, MD6; Raphaël Heinzer, MD2; José Haba-Rubio, MD2; Eva Feketeova, MD19; Birgit Högl, MD20; Birgit Frauscher, MD20; Antonio Benetó, MD21; Ramin Khatami, MD22; Francesca Cañellas, MD23; Corinne Pfister, MSc1; Sabine Scholz5; Michel Billiard, MD5; Christian R. Baumann, MD24; Guadalupe Ercilla, MD25; Willem Verduijn, BSc26; Frans H.J. Claas, PhD26; Valérie Dubois, MD27; Jacek Nowak, PhD28; Hans-Peter Eberhard, PhD29; Sylvain Pradervand, PhD30,31; Charlotte N. Hor, PhD3; Manuela Testi, PhD32; Jean-Marie Tiercy, PhD33; Zoltán Kutalik, PhD31,34,35

1Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland; 2Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland; 3Center for Genomic Regulation (CRG), Barcelona, and Universitat Pompeu Fabra (UPF), Barcelona, Spain; 4INSERM-1061, Montpellier, France; 5National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Guide-Chauliac Hospital, Montpellier, France; 6Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands; 7Sleep-Wake Center SEIN, Heemstede, The Netherlands; 8Sleep Medicine Center ‘Kempenhaeghe’, Heeze, The Netherlands; 9Hephata-Clinic for Neurology, Schwalmstadt-Treysa, Germany; 10Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain; 11Sleep and Epilepsy Unit - Clinical Neurophysiology Department, Gregorio Marañón University Hospital, Madrid, Spain; 12Histocompatibility, Blood Center of the Community of Madrid, Madrid, Spain; 13National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Sleep disorders unit, Pitié-Salpêtrière Hospital, Paris, France; 14Department of Biomedical and NeuroMotor Sciences, University of Bologna and IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna Italy; 15Sleep Disorders and Research Center, Department of Psychiatry and Psychotherapy, University Hospital Regensburg, Regensburg, Germany; 16Institute of Psychiatry and Neurology, Department of Clinical Neurophysiology and Sleep Disorders Center, Warsaw, Poland; 17Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland; 18Pediatric Sleep Center, National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Robert Debré Hospital, Paris VII University, Paris, France; 19Department of Neurology, Faculty of Medicine, Safarikiensis University and Louis Pasteur Faculty Hospital Kosice, Kosice, Slovakia; 20Department of Neurology, Innsbruck Medical University, Innsbruck, Austria; 21Unidad de Sueño, Servicio Neurofisiología Clínica, Hospital Universitario La Fe, Valencia, Spain; 22Sleep Medicine, Barmelweid Clinic, Switzerland; 23Servicio de Psiquiatría, Hospital Universitario Son Espases, Palma de Mallorca, Spain; 24Department of Neurology, University Hospital Zurich, Switzerland; 25Immunology Service, CDB, Hospital Clinic, Barcelona, Spain; 26Department of Immunohaematology and Blood Trans-fusion, Leiden University Medical Centre, The Netherlands; 27HLA Laboratory, Etablissement Français du Sang, Lyon, France; 28Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; 29German National Bone Marrow Donor Registry, Ulm, Germany; 30Lausanne Genomic Technologies Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland; 31Swiss Institute of Bioinformatics, Lausanne, Switzerland; 32Laboratory of Immunogenetics and Transplant Biology, IME Foundation-Mediterranean Institute of Hematology, Roma, Italy; 33National Reference Laboratory for Histocompatibility, Transplantation Immunology Unit, Department of Genetics and Laboratory Medicine, University Hospital Geneva, Geneva, Switzerland; 34Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; 35Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

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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.


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 < 2x10-9) and rs1154155 within the TRA locus (P < 2x10-8) 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.

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