Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Anesthesia Critical Care and Pain Medicine Massachusetts General Hospital and Harvard Medical School Boston MA USA

Center for Advanced Research in Sleep Medicine Hôpital du Sacré Coeur and Department of Neurosciences University of Montréal Montréal QC Canada

Center for Applied Biomedical Research St Orsola Malpighi University Hospital Bologna Italy

Center for Genomic Medicine Massachusetts General Hospital Boston MA USA

Center for Sleep Medicine and Sleep Research Clinic Barmelweid AG Barmelweid Switzerland

Charité Universitätsmedizin Berlin Einstein Center for Neurosciences Berlin 10117 Berlin Germany

Coliseum on Majorstua Clinic Oslo Norway

Danish Center for Sleep Medicine Department of Clinical Neurophysiology University of Copenhagen Glostrup Hospital Glostrup Denmark

Department of Biology Stanford University Stanford CA 94305 USA

Department of Biomedical and Neuromotor Sciences University of Bologna Via Ugo Foscolo 7 40123 Bologna Italy

Department of Biomedical Data Science Administration Stanford University Palo Alto CA USA

Department of Child Psychiatry and Sleep Center Chang Gung Memorial Hospital and University Taoyuan Taiwan

Department of Clinical Neurophysiology Institute of Psychiatry and Neurology Warsaw Poland

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Clinical Neurosciences University of Helsinki Helsinki Finland

Department of Epidemiology and Biostatistics Institute for Human Genetics University of California San Francisco San Francisco CA USA

Department of Genetics Stanford University Stanford CA 94305 USA

Department of Human Genetics Graduate School of Medicine The University of Tokyo Tokyo Japan

Department of Medical Sciences and Science for Life Laboratory Uppsala University Uppsala Sweden

Department of Neurology and Centre of Clinical Neurosciences 1st Faculty of Medicine Charles University and General University Hosptal Prague Czech Republic

Department of Neurology Barcelona Spain

Department of Neurology Charité Universitätsmedizin 10117 Berlin Germany

Department of Neurology Emory University School of Medicine Atlanta GA USA

Department of Neurology Inselspital Bern University Hospital and University of Bern Bern Switzerland

Department of Neurology Leiden University Medical Center Leiden The Netherlands

Department of Neurology Medical University Innsbruck Innsbruck Austria

Department of Neurology The Peking University People's Hospital Beijing China

Department of Neuropsychiatry Akita University Graduate School of Medicine Akita Japan

Department of Neuroscience University of Copenhagen Copenhagen Denmark

Department of Pediatric Genetics Amrita Institute of Medical Sciences and Research Centre Kerala India

Department of Psychiatry and Behavioral Sciences Stanford University Palo Alto CA USA

Department of Psychiatry and Behavioral Sciences Tokyo Metropolitan Institute of Medical Science Tokyo Japan

Department of Psychiatry and Psychotherapy University of Regensburg Regensburg Germany

Department of Psychiatry St Vincent's Hospital The Catholic University of Korea Suwon Korea

Department of Sleep Medicine Strasbourg University Hospital Strasbourg University Strasbourg France

Dept Epidemiology and Biostatistics UCSF 513 Parnassus Avenue San Francisco CA 94117 USA

Division of Child and Adolescent Psychiatry Karolinska Institutet Stockholm Sweden

Division of Research Kaiser Permanente Northern California Oakland CA USA

Division of Sleep Medicine The Peking University People's Hospital Beijing China

Eindhoven University of Technology Eindhoven The Netherlands

Faculty of Health Sciences Hasan Kalyoncu University Gaziantep Turkey

Helsinki Sleep Clinic Vitalmed Research Centre Helsinki Finland

Hephata Klinik Schimmelpfengstr 6 34613 Schwalmstadt Germany

Hormone Laboratory Department of Medical Biochemistry Oslo University Hospital Oslo Norway

Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain

Institute for Molecular Medicine Finland HiLIFE University of Helsinki Helsinki Finland

Institute of Neurogenomics Helmholtz Zentrum München German Research Centre for Environmental Health Neuherberg Germany

International Institute for Integrative Sleep Medicine University of Tsukuba Tsukuba Japan

IRCCS Institute of Neurological Sciences Bologna Italy

Mater Private Hospital Dublin 7 Ireland

Mental Illness Research Education Clinical Centers VA Palo Alto Palo Alto CA USA

Multidisciplinary Sleep Disorders Unit Barcelona Spain

Munich Cluster for Systems Neurology Munich Germany

Neurologische Klinik und Poliklinik Klinikum rechts der Isar der Technischen Universität München Munich Germany

Neurology Department EOC Ospedale Regionale di Lugano Lugano Ticino Switzerland

Neurology Department Medical Faculty of P J Safarik University University Hospital of L Pasteur Kosice Kosice Slovak Republic

Neurology Service Institut de Neurociències Hospital Clínic University of Barcelona Barcelona Spain

Norwegian Centre of Expertise for Neurodevelopment Disorders and Hypersomnias Department of Rare Disorders Oslo University Hospital and University of Oslo Oslo Norway

Pediatric Sleep Center and National Reference Center for Narcolepsy and Idiopathic Hypersomnia Hospital Robert Debre Paris France

Philipps Universität Marburg Baldinger Str 35043 Marburg Germany

Seiwa Hospital Neuropsychiatric Research Institute Tokyo Japan

Shaare Zedek Medical Center Jerusalem Israel

Sleep and Epilepsy Unit Clinical Neurophysiology Service Gregorio Marañón University General Hospital and Research Institute University Complutense of Madrid Madrid Spain

Sleep Disorder Unit Pitié Salpêtrière Hospital Assistance Publique Hopitaux de Paris 75013 Paris France

Sleep Disorders Center Division of Neuroscience Ospedale San Raffaele Università Vita Salute Milan Italy

Sleep Medicine Center Kempenhaeghe P O Box 61 5590 AB Heeze The Netherlands

Sleep Unit Clinical Neurophysiology Service San Carlos University Hospital University Complutense of Madrid Madrid Spain

Sleep Unit Medical Center Valencia Valencia Spain

Sleep Wake Disorders Center National Reference Network for Narcolepsy Department of Neurology Gui de Chauliac Hospital CHU Montpellier; Institute for Neurosciences of Montpellier INSERM Université Montpellier 1 Montpellier France

Stanford University Center for Sleep Sciences and Medicine Department of Psychiatry and Behavioral Sciences Palo Alto CA 94304 USA

Stichting Epilepsie Instellingen Nederland Sleep Wake Centre Heemstede The Netherlands

Swiss Institute of Bioinformatics Lausanne Switzerland

Universidade Federal de São Paulo Departamento de Psicobiologia São Paulo Brazil

University Center for Primary Care and Public Health University of Lausanne Lausanne Switzerland Lausanne 1010 Switzerland

University of Helsinki Institute for Molecular Medicine Finland and Diabetes and Obesity Research Program University of Tartu Estonian Genome Center Tartu Estonia

Uppsala Clinical Research Center Uppsala Sweden

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