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. Eeden, Michel Lecendreux, Patrice Bourgin, Takashi Kanbayashi, Francisco J. Martínez-Orozco, Rosa Peraita-Adrados, Antonio Benetó, Jacques Montplaisir, Alex Desautels, Yu-Shu Huang, 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 and Emmanuel J. Mignot ()
Additional contact information
Hanna M. Ollila: Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
Eilon Sharon: Stanford University
Ling Lin: Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
Nasa Sinnott-Armstrong: 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: 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: The Peking University People’s Hospital
Han Yan: The Peking University People’s Hospital
Xiao Song Dong: The Peking University People’s Hospital
Jing Li: The Peking University People’s Hospital
Jun Zhang: The Peking University People’s Hospital
Seung-Chul Hong: The Catholic University of Korea
Tae Won Kim: The Catholic University of Korea
Yves Dauvilliers: Gui-de-Chauliac Hospital, CHU Montpellier; Institute for Neurosciences of Montpellier (INM), INSERM, Université Montpellier 1
Lucie Barateau: Gui-de-Chauliac Hospital, CHU Montpellier; Institute for Neurosciences of Montpellier (INM), INSERM, Université Montpellier 1
Gert Jan Lammers: Leiden University Medical Center
Rolf Fronczek: Leiden University Medical Center
Geert Mayer: Hephata Klinik
Joan Santamaria: University of Barcelona
Isabelle Arnulf: Sleep Disorder Unit, Pitié-Salpêtrière Hospital, Assistance Publique—Hopitaux de Paris
Stine Knudsen-Heier: Oslo University Hospital and University of Oslo
May Kristin Lyamouri Bredahl: Oslo University Hospital and University of Oslo
Per Medbøe Thorsby: Oslo University Hospital
Giuseppe Plazzi: University of Bologna
Fabio Pizza: University of Bologna
Monica Moresco: University of Bologna
Catherine Crowe: Mater Private Hospital
Stephen K. 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: Strasbourg University Hospital, Strasbourg University
Takashi Kanbayashi: 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: Gregorio Marañón University General Hospital and Research Institute, University Complutense of Madrid (UCM)
Antonio Benetó: Sleep Unit. Medical Center Valencia
Jacques Montplaisir: University of Montréal
Alex Desautels: University of Montréal
Yu-Shu Huang: Chang Gung Memorial Hospital and University
Poul Jennum: University of Copenhagen, Glostrup Hospital
Sona Nevsimalova: Charles University and General University Hosptal
David Kemlink: 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: Institute of Psychiatry and Neurology
Peter Geisler: University of Regensburg
Karel Sonka: Charles University and General University Hosptal
Makoto Honda: Tokyo Metropolitan Institute of Medical Science
Birgit Högl: Medical University Innsbruck (MUI)
Ambra Stefani: Medical University Innsbruck (MUI)
Fernando Morgadinho Coelho: Universidade Federal de São Paulo, Departamento de Psicobiologia
Vilma Mantovani: St. Orsola-Malpighi University Hospital
Eva Feketeova: Medical Faculty of P. J. Safarik University, University Hospital of L. Pasteur Kosice
Mia Wadelius: Uppsala University
Niclas Eriksson: Uppsala University
Hans Smedje: Karolinska Institutet
Pär Hallberg: Uppsala University
Per Egil Hesla: Coliseum on Majorstua Clinic
David Rye: Emory University School of Medicine
Zerrin Pelin: Hasan Kalyoncu University
Luigi Ferini-Strambi: Università Vita-Salute
Claudio L. Bassetti: EOC, Ospedale Regionale di Lugano
Johannes Mathis: Bern University Hospital, and University of Bern
Ramin Khatami: Bern University Hospital, and University of Bern
Adi Aran: Shaare Zedek Medical Center
Sheela Nampoothiri: Amrita Institute of Medical Sciences & Research Centre
Tomas Olsson: Karolinska Institutet
Ingrid Kockum: Karolinska Institutet
Markku Partinen: 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: 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: Tokyo Metropolitan Institute of Medical Science
Hiromi Toyoda: Tokyo Metropolitan Institute of Medical Science
Seik-Soon Khor: The University of Tokyo
Mihoko Shimada: The University of Tokyo
Katsushi Tokunaga: The University of Tokyo
Manuel Rivas: Stanford University
Jonathan K. Pritchard: Stanford University
Neil Risch: UCSF
Zoltan Kutalik: Swiss Institute of Bioinformatics
Ruth O’Hara: Stanford University
Joachim Hallmayer: Stanford University
Chun Jimmie Ye: University of California San Francisco
Emmanuel J. Mignot: Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences

Nature Communications, 2023, vol. 14, issue 1, 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®.

Date: 2023
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DOI: 10.1038/s41467-023-36120-z

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