DQB1 LOCUS AND THE RISK AND PROTECTION IN NARCOLEPSY WITH CATAPLEXY
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
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.