Nature Communications (May 2023)
Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy
- Hanna M. Ollila,
- Eilon Sharon,
- Ling Lin,
- Nasa Sinnott-Armstrong,
- Aditya Ambati,
- Selina M. Yogeshwar,
- Ryan P. Hillary,
- Otto Jolanki,
- Juliette Faraco,
- Mali Einen,
- Guo Luo,
- Jing Zhang,
- Fang Han,
- Han Yan,
- Xiao Song Dong,
- Jing Li,
- Jun Zhang,
- Seung-Chul Hong,
- Tae Won Kim,
- Yves Dauvilliers,
- Lucie Barateau,
- Gert Jan Lammers,
- Rolf Fronczek,
- Geert Mayer,
- Joan Santamaria,
- Isabelle Arnulf,
- Stine Knudsen-Heier,
- May Kristin Lyamouri Bredahl,
- Per Medbøe Thorsby,
- Giuseppe Plazzi,
- Fabio Pizza,
- Monica Moresco,
- Catherine Crowe,
- Stephen K. Van den Eeden,
- Michel Lecendreux,
- Patrice Bourgin,
- Takashi Kanbayashi,
- Francisco J. Martínez-Orozco,
- Rosa Peraita-Adrados,
- Antonio Benetó,
- Jacques Montplaisir,
- Alex Desautels,
- Yu-Shu Huang,
- FinnGen,
- Poul Jennum,
- Sona Nevsimalova,
- David Kemlink,
- Alex Iranzo,
- Sebastiaan Overeem,
- Aleksandra Wierzbicka,
- Peter Geisler,
- Karel Sonka,
- Makoto Honda,
- Birgit Högl,
- Ambra Stefani,
- Fernando Morgadinho Coelho,
- Vilma Mantovani,
- Eva Feketeova,
- Mia Wadelius,
- Niclas Eriksson,
- Hans Smedje,
- Pär Hallberg,
- Per Egil Hesla,
- David Rye,
- Zerrin Pelin,
- Luigi Ferini-Strambi,
- Claudio L. Bassetti,
- Johannes Mathis,
- Ramin Khatami,
- Adi Aran,
- Sheela Nampoothiri,
- Tomas Olsson,
- Ingrid Kockum,
- Markku Partinen,
- Markus Perola,
- Birgitte R. Kornum,
- Sina Rueger,
- Juliane Winkelmann,
- Taku Miyagawa,
- Hiromi Toyoda,
- Seik-Soon Khor,
- Mihoko Shimada,
- Katsushi Tokunaga,
- Manuel Rivas,
- Jonathan K. Pritchard,
- Neil Risch,
- Zoltan Kutalik,
- Ruth O’Hara,
- Joachim Hallmayer,
- Chun Jimmie Ye,
- Emmanuel J. Mignot
Affiliations
- Hanna M. Ollila
- Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
- Eilon Sharon
- Department of Genetics, Stanford University
- Ling Lin
- Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
- Nasa Sinnott-Armstrong
- Department of Genetics, Stanford University
- Aditya Ambati
- Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
- Selina M. Yogeshwar
- Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
- Ryan P. Hillary
- Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
- Otto Jolanki
- Department of Genetics, Stanford University
- Juliette Faraco
- Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
- Mali Einen
- Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
- Guo Luo
- Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
- Jing Zhang
- Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
- Fang Han
- Division of Sleep Medicine, The Peking University People’s Hospital
- Han Yan
- Division of Sleep Medicine, The Peking University People’s Hospital
- Xiao Song Dong
- Division of Sleep Medicine, The Peking University People’s Hospital
- Jing Li
- Division of Sleep Medicine, The Peking University People’s Hospital
- Jun Zhang
- Department of Neurology, The Peking University People’s Hospital
- Seung-Chul Hong
- Department of Psychiatry, St. Vincent’s Hospital, The Catholic University of Korea
- Tae Won Kim
- Department of Psychiatry, St. Vincent’s Hospital, The Catholic University of Korea
- Yves Dauvilliers
- Sleep-Wake Disorders Center, National Reference Network for Narcolepsy, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier; Institute for Neurosciences of Montpellier (INM), INSERM, Université Montpellier 1
- Lucie Barateau
- Sleep-Wake Disorders Center, National Reference Network for Narcolepsy, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier; Institute for Neurosciences of Montpellier (INM), INSERM, Université Montpellier 1
- Gert Jan Lammers
- Department of Neurology, Leiden University Medical Center
- Rolf Fronczek
- Department of Neurology, Leiden University Medical Center
- Geert Mayer
- Hephata Klinik
- Joan Santamaria
- Neurology Service, Institut de Neurociències Hospital Clínic, University of Barcelona
- Isabelle Arnulf
- Sleep Disorder Unit, Pitié-Salpêtrière Hospital, Assistance Publique—Hopitaux de Paris
- Stine Knudsen-Heier
- Norwegian Centre of Expertise for Neurodevelopment Disorders and Hypersomnias (NevSom), Department of Rare Disorders, Oslo University Hospital and University of Oslo
- May Kristin Lyamouri Bredahl
- Norwegian Centre of Expertise for Neurodevelopment Disorders and Hypersomnias (NevSom), Department of Rare Disorders, Oslo University Hospital and University of Oslo
- Per Medbøe Thorsby
- Hormone Laboratory, Department of Medical Biochemistry, Oslo University Hospital
- Giuseppe Plazzi
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna
- Fabio Pizza
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna
- Monica Moresco
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna
- Catherine Crowe
- Mater Private Hospital
- Stephen K. Van den Eeden
- Division of Research, Kaiser Permanente Northern California
- Michel Lecendreux
- Pediatric Sleep Center and National Reference Center for Narcolepsy and Idiopathic Hypersomnia Hospital Robert Debre
- Patrice Bourgin
- Department of Sleep Medicine, Strasbourg University Hospital, Strasbourg University
- Takashi Kanbayashi
- Department of Neuropsychiatry, Akita University Graduate School of Medicine
- Francisco J. Martínez-Orozco
- Sleep Unit. Clinical Neurophysiology Service. San Carlos University Hospital. University Complutense of Madrid
- Rosa Peraita-Adrados
- Sleep and Epilepsy Unit, Clinical Neurophysiology Service, Gregorio Marañón University General Hospital and Research Institute, University Complutense of Madrid (UCM)
- Antonio Benetó
- Sleep Unit. Medical Center Valencia
- Jacques Montplaisir
- Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Neurosciences, University of Montréal
- Alex Desautels
- Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Neurosciences, University of Montréal
- Yu-Shu Huang
- Department of Child Psychiatry and Sleep Center, Chang Gung Memorial Hospital and University
- FinnGen
- Poul Jennum
- Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital
- Sona Nevsimalova
- Department of Neurology and Centre of Clinical Neurosciences, First Faculty of Medicine, Charles University and General University Hosptal
- David Kemlink
- Department of Neurology and Centre of Clinical Neurosciences, First Faculty of Medicine, Charles University and General University Hosptal
- Alex Iranzo
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
- Sebastiaan Overeem
- Sleep Medicine Center Kempenhaeghe
- Aleksandra Wierzbicka
- Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology
- Peter Geisler
- Department of Psychiatry and Psychotherapy, University of Regensburg
- Karel Sonka
- Department of Neurology and Centre of Clinical Neurosciences, First Faculty of Medicine, Charles University and General University Hosptal
- Makoto Honda
- Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science
- Birgit Högl
- Department of Neurology, Medical University Innsbruck (MUI)
- Ambra Stefani
- Department of Neurology, Medical University Innsbruck (MUI)
- Fernando Morgadinho Coelho
- Universidade Federal de São Paulo, Departamento de Psicobiologia
- Vilma Mantovani
- Center for Applied Biomedical Research (CRBA), St. Orsola-Malpighi University Hospital
- Eva Feketeova
- Neurology Department, Medical Faculty of P. J. Safarik University, University Hospital of L. Pasteur Kosice
- Mia Wadelius
- Department of Medical Sciences and Science for Life Laboratory, Uppsala University
- Niclas Eriksson
- Department of Medical Sciences and Science for Life Laboratory, Uppsala University
- Hans Smedje
- Division of Child and Adolescent Psychiatry, Karolinska Institutet
- Pär Hallberg
- Department of Medical Sciences and Science for Life Laboratory, Uppsala University
- Per Egil Hesla
- Coliseum on Majorstua Clinic
- David Rye
- Department of Neurology, Emory University School of Medicine
- Zerrin Pelin
- Faculty of Health Sciences, Hasan Kalyoncu University
- Luigi Ferini-Strambi
- Sleep Disorders Center, Division of Neuroscience, Ospedale San Raffaele, Università Vita-Salute
- Claudio L. Bassetti
- Neurology Department, EOC, Ospedale Regionale di Lugano
- Johannes Mathis
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern
- Ramin Khatami
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern
- Adi Aran
- Shaare Zedek Medical Center
- Sheela Nampoothiri
- Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre
- Tomas Olsson
- Department of Clinical Neuroscience, Karolinska Institutet
- Ingrid Kockum
- Department of Clinical Neuroscience, Karolinska Institutet
- Markku Partinen
- Helsinki Sleep Clinic, Vitalmed Research Centre
- Markus Perola
- University of Helsinki, Institute for Molecular Medicine, Finland (FIMM) and Diabetes and Obesity Research Program. University of Tartu, Estonian Genome Center
- Birgitte R. Kornum
- Department of Neuroscience, University of Copenhagen
- Sina Rueger
- Swiss Institute of Bioinformatics
- Juliane Winkelmann
- Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health
- Taku Miyagawa
- Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science
- Hiromi Toyoda
- Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science
- Seik-Soon Khor
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo
- Mihoko Shimada
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo
- Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo
- Manuel Rivas
- Department of Biomedical Data Science-Administration, Stanford University
- Jonathan K. Pritchard
- Department of Genetics, Stanford University
- Neil Risch
- Dept. Epidemiology and Biostatistics, UCSF
- Zoltan Kutalik
- Swiss Institute of Bioinformatics
- Ruth O’Hara
- Department of Psychiatry and Behavioral Sciences, Stanford University
- Joachim Hallmayer
- Department of Psychiatry and Behavioral Sciences, Stanford University
- Chun Jimmie Ye
- Department of Epidemiology & Biostatistics, Institute for Human Genetics, University of California San Francisco
- Emmanuel J. Mignot
- Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
- DOI
- https://doi.org/10.1038/s41467-023-36120-z
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 13
Abstract
Abstract 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®.
