title: DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.
abstract: 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.
  
  
  METHODS
  Retrospective case-control study.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland ; Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Tafti
authors.affiliation: Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland ; Center for Genomic Regulation (CRG), Barcelona, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Hyun
authors.initials: H
authors.lastname: Hor
authors.affiliation: INSERM-1061, Montpellier, France ; National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Guide-Chauliac Hospital, Montpellier, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Dauvilliers
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands ; Sleep-Wake Center SEIN, Heemstede, The Netherlands.
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Lammers
authors.affiliation: Sleep Medicine Center 'Kempenhaeghe', Heeze, The Netherlands.
authors.forename: Sebastiaan
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authors.affiliation: Hephata-Clinic for Neurology, Schwalmstadt-Treysa, Germany.
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authors.affiliation: Hephata-Clinic for Neurology, Schwalmstadt-Treysa, Germany.
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authors.affiliation: Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain.
authors.forename: Alex
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authors.affiliation: Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain.
authors.forename: Joan
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authors.lastname: Santamaria
authors.affiliation: Sleep and Epilepsy Unit - Clinical Neurophysiology Department, Gregorio Marañón University Hospital, Madrid, Spain.
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authors.affiliation: Histocompatibility, Blood Center of the Community of Madrid, Madrid, Spain.
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authors.initials: JL
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authors.affiliation: National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Sleep disorders unit, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Arnulf
authors.affiliation: Department of Biomedical and NeuroMotor Sciences, University of Bologna and IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna Italy.
authors.forename: Giuseppe
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authors.lastname: Plazzi
authors.affiliation: INSERM-1061, Montpellier, France ; National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Guide-Chauliac Hospital, Montpellier, France.
authors.forename: Sophie
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authors.lastname: Bayard
authors.affiliation: Department of Biomedical and NeuroMotor Sciences, University of Bologna and IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Poli
authors.affiliation: Department of Biomedical and NeuroMotor Sciences, University of Bologna and IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pizza
authors.affiliation: Sleep Disorders and Research Center, Department of Psychiatry and Psychotherapy, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Peter
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authors.lastname: Geisler
authors.affiliation: Institute of Psychiatry and Neurology, Department of Clinical Neurophysiology and Sleep Disorders Center, Warsaw, Poland.
authors.forename: Aleksandra
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authors.affiliation: Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Claudio L
authors.initials: CL
authors.lastname: Bassetti
authors.affiliation: Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Johannes
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authors.forename: Michel
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authors.lastname: Lecendreux
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Claire E H M
authors.initials: CE
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authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Astrid
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authors.affiliation: Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Raphaël
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authors.affiliation: Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: José
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authors.affiliation: Department of Neurology, Faculty of Medicine, Safarikiensis University and Louis Pasteur Faculty Hospital Kosice, Kosice, Slovakia.
authors.forename: Eva
authors.initials: E
authors.lastname: Feketeova
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
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authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Birgit
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authors.affiliation: Unidad de Sueño, Servicio Neurofisiología Clínica, Hospital Universitario La Fe, Valencia, Spain.
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authors.affiliation: Sleep Medicine, Barmelweid Clinic, Switzerland.
authors.forename: Ramin
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authors.affiliation: Servicio de Psiquiatría, Hospital Universitario Son Espases, Palma de Mallorca, Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cañellas
authors.affiliation: Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Pfister
authors.affiliation: National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Guide-Chauliac Hospital, Montpellier, France.
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authors.affiliation: National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Guide-Chauliac Hospital, Montpellier, France.
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authors.lastname: Billiard
authors.affiliation: Department of Neurology, University Hospital Zurich, Switzerland.
authors.forename: Christian R
authors.initials: CR
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authors.affiliation: Immunology Service, CDB, Hospital Clinic, Barcelona, Spain.
authors.forename: Guadalupe
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authors.lastname: Ercilla
authors.affiliation: Department of Immunohaematology and Blood Trans-fusion, Leiden University Medical Centre, The Netherlands.
authors.forename: Willem
authors.initials: W
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authors.affiliation: Department of Immunohaematology and Blood Trans-fusion, Leiden University Medical Centre, The Netherlands.
authors.forename: Frans H J
authors.initials: FH
authors.lastname: Claas
authors.affiliation: HLA Laboratory, Etablissement Français du Sang, Lyon, France.
authors.forename: Valérie
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authors.affiliation: Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Jacek
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authors.affiliation: German National Bone Marrow Donor Registry, Ulm, Germany.
authors.forename: Hans-Peter
authors.initials: HP
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authors.affiliation: Lausanne Genomic Technologies Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland ; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Sylvain
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authors.lastname: Pradervand
authors.affiliation: Center for Genomic Regulation (CRG), Barcelona, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Charlotte N
authors.initials: CN
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authors.affiliation: Laboratory of Immunogenetics and Transplant Biology, IME Foundation-Mediterranean Institute of Hematology, Roma, Italy.
authors.forename: Manuela
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authors.affiliation: National Reference Laboratory for Histocompatibility, Transplantation Immunology Unit, Department of Genetics and Laboratory Medicine, University Hospital Geneva, Geneva, Switzerland.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Tiercy
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland ; Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland ; Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Zoltán
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mesh_terms: D000483:Alleles; D002385:Cataplexy / Q000235:genetics*; D003850:Deoxyribonuclease I / Q000378:metabolism; D005060:Europe / Q000453:epidemiology / Q000208:ethnology; D059472:Exome / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage; D009290:Narcolepsy / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D014611:Vaccination; D044465:White People / Q000235:genetics
chemical_list: D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D007252:Influenza Vaccines; D003850:Deoxyribonuclease I
keywords: Autoimmunity; GWAS; H1N1 vaccination; genetics