Mehdi Tafti1, Hyun Hor2, Yves Dauvilliers3, Gert J Lammers4, Sebastiaan Overeem5, Geert Mayer6, Sirous Javidi6, Alex Iranzo7, Joan Santamaria7, Rosa Peraita-Adrados8, José L Vicario9, Isabelle Arnulf10, Giuseppe Plazzi11, Sophie Bayard3, Francesca Poli11, Fabio Pizza11, Peter Geisler12, Aleksandra Wierzbicka13, Claudio L Bassetti14, Johannes Mathis14, Michel Lecendreux15, Claire E H M Donjacour16, Astrid van der Heide16, Raphaël Heinzer17, José Haba-Rubio17, Eva Feketeova18, Birgit Högl19, Birgit Frauscher19, Antonio Benetó20, Ramin Khatami21, Francesca Cañellas22, Corinne Pfister23, Sabine Scholz24, Michel Billiard24, Christian R Baumann25, Guadalupe Ercilla26, Willem Verduijn27, Frans H J Claas27, Valérie Dubois28, Jacek Nowak29, Hans-Peter Eberhard30, Sylvain Pradervand31, Charlotte N Hor32, Manuela Testi33, Jean-Marie Tiercy34, Zoltán Kutalik35. 1. 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. 2. Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland ; Center for Genomic Regulation (CRG), Barcelona, and Universitat Pompeu Fabra (UPF), Barcelona, Spain. 3. INSERM-1061, Montpellier, France ; National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Guide-Chauliac Hospital, Montpellier, France. 4. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands ; Sleep-Wake Center SEIN, Heemstede, The Netherlands. 5. Sleep Medicine Center 'Kempenhaeghe', Heeze, The Netherlands. 6. Hephata-Clinic for Neurology, Schwalmstadt-Treysa, Germany. 7. Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. 8. Sleep and Epilepsy Unit - Clinical Neurophysiology Department, Gregorio Marañón University Hospital, Madrid, Spain. 9. Histocompatibility, Blood Center of the Community of Madrid, Madrid, Spain. 10. National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Sleep disorders unit, Pitié-Salpêtrière Hospital, Paris, France. 11. Department of Biomedical and NeuroMotor Sciences, University of Bologna and IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna Italy. 12. Sleep Disorders and Research Center, Department of Psychiatry and Psychotherapy, University Hospital Regensburg, Regensburg, Germany. 13. Institute of Psychiatry and Neurology, Department of Clinical Neurophysiology and Sleep Disorders Center, Warsaw, Poland. 14. Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. 15. Pediatric Sleep Center, National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Robert Debré Hospital, Paris VII University, Paris, France. 16. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. 17. Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. 18. Department of Neurology, Faculty of Medicine, Safarikiensis University and Louis Pasteur Faculty Hospital Kosice, Kosice, Slovakia. 19. Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. 20. Unidad de Sueño, Servicio Neurofisiología Clínica, Hospital Universitario La Fe, Valencia, Spain. 21. Sleep Medicine, Barmelweid Clinic, Switzerland. 22. Servicio de Psiquiatría, Hospital Universitario Son Espases, Palma de Mallorca, Spain. 23. Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland. 24. National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Guide-Chauliac Hospital, Montpellier, France. 25. Department of Neurology, University Hospital Zurich, Switzerland. 26. Immunology Service, CDB, Hospital Clinic, Barcelona, Spain. 27. Department of Immunohaematology and Blood Trans-fusion, Leiden University Medical Centre, The Netherlands. 28. HLA Laboratory, Etablissement Français du Sang, Lyon, France. 29. Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland. 30. German National Bone Marrow Donor Registry, Ulm, Germany. 31. Lausanne Genomic Technologies Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland ; Swiss Institute of Bioinformatics, Lausanne, Switzerland. 32. Center for Genomic Regulation (CRG), Barcelona, and Universitat Pompeu Fabra (UPF), Barcelona, Spain. 33. Laboratory of Immunogenetics and Transplant Biology, IME Foundation-Mediterranean Institute of Hematology, Roma, Italy. 34. National Reference Laboratory for Histocompatibility, Transplantation Immunology Unit, Department of Genetics and Laboratory Medicine, University Hospital Geneva, Geneva, Switzerland. 35. 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.
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-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. CONCLUSION: 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.
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 narcolepsypatients 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. CONCLUSION: 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.
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Authors: Anna Heidbreder; Birgit Frauscher; Thomas Mitterling; Matthias Boentert; Anja Schirmacher; Paul Hörtnagl; Harald Schennach; Christina Massoth; Svenja Happe; Geert Mayer; Peter Young; Birgit Högl Journal: J Clin Sleep Med Date: 2016-04-15 Impact factor: 4.062