Hyun Hor^1,2,28, Zoltan Kutalik^3,4,28, Yves Dauvilliers^2,5, Armand Valsesia^3,4,6, Gert J Lammers⁷, Claire E H M Donjacour⁷, Alex Iranzo⁸, Joan Santamaria⁸, Rosa Peraita Adrados⁹, Jose L Vicario¹⁰, Sebastiaan Overeem^11,12, Isabelle Arnulf¹³, Ioannis Theodorou¹⁴, Poul Jennum¹⁵, Stine Knudsen¹⁵, Claudio Bassetti¹⁶, Johannes Mathis¹⁷, Michel Lecendreux¹⁸, Geert Mayer¹⁹, Peter Geisler²⁰, Antonio Beneto²¹, Brice Petit¹, Corinne Pfister¹, Julie Vienne Burki¹, Gerard Didelot¹, Michel Billiard⁵, Guadalupe Ercilla²², Willem Verduijn²³, Frans H J Claas²³, Peter Vollenwider²⁴, Gerard Waeber²⁴, Dawn M Waterworth²⁵, Vincent Mooser²⁵, Raphael Heinzer²⁶, Jacques S Beckmann^3,27, Sven Bergmann^3,4 & Mehdi Tafti^1,26

¹Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. ²Institut National de la Sante et de la Recherche Medicale U888, Montpellier, France. ³Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. ⁴Swiss Institute of Bioinformatics, Lausanne, Switzerland. ⁵National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Gui-de-Chauliac Hospital, Montpellier, France. ⁶Ludwig Institute for Cancer Research, Lausanne, Switzerland. ⁷Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands. ⁸Neurology Service, Hospital Clinic, Institut d’Investigacio Biomediques August Pi i Sunyer, and Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain. ⁹Sleep and Epilepsy Unit, Clinical Neurophysiology Department, Gregorio Maranon University Hospital, Madrid, Spain. ¹⁰Histocompatibility, Blood Center of the Community of Madrid, Madrid, Spain. ¹¹Sleep Medicine Center ‘Kempenhaeghe’, Heeze, The Netherlands. ¹²Department of Neurology, Donders Institute for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. ¹³National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Sleep Disorders Unit, Pitie-Salpetriere Hospital, Paris, France. ¹⁴Institut National de la Sante et de la Recherche Medicale U543, Pitie-Salpetriere Hospital, Paris, France. ¹⁵Department of Clinical Neurophysiology, University of Copenhagen, Glostrup, Denmark. ¹⁶Neurocentro (Ente ospedaliero cantonale) della Svizzera Italiana, Ospedale Civico, Lugano, Switzerland. ¹⁷Abteilung Klinische Neurophysiologie, Inselspital, Bern, Switzerland. ¹⁸Pediatric Sleep Center, National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Child and Adolescent Psychopathology, Robert Debre Hospital, Paris VII University, Paris, France. ¹⁹Hephata-Clinic for Neurology, Schwalmstadt-Treysa, Germany. ²⁰Sleep Disorders and Research Center, Department of Psychiatry and Psychotherapy, University Hospital Regensburg, Regensburg, Germany. ²¹Unidad de Sueno, Servicio Neurofisiologia Clinica, Hospital Universitario La Fe, Valencia, Spain. ²²Immunology Service, Institut d’Investigacio Biomediques August Pi i Sunyer, Hospital Clinic, Barcelona, Spain. ²³Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands. ²⁴Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. ²⁵Division of Genetics, Research and Development, GlaxoSmithKline, King of Prussia, Pennsylvania, USA. ²⁶Center for Investigation and Research in Sleep, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. ²⁷Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. ²⁸These authors contributed equally to this work. Correspondence should be addressed to M.T.

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 × 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.