Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

• Type of Material: Article
• Authors: HM Ollila, Stanford University; Eilon Sharon, Stanford University; Ling Lin, Stanford University; Nasa Sinnott-Armstrong, Stanford University; Aditya Ambati, Stanford University; Selina M Yogeshwar, Stanford University; Ryan P Hillary, Stanford University; Otto Jolanki, Stanford University; Juliette Faraco, Stanford University; Mali Einen, Stanford University; Guo Luo, Stanford University; Jing Zhang, Stanford University; Fang Han, Peking University People's Hospital; Hann Yan, Peking University People's Hospital; Xiao Song Dong, Peking University People's Hospital; Jing Li, Peking University People's Hospital; Jun Zhang, Peking University People's Hospital; Seung-Chul Hong, The Catholic University of Korea, St. Vincent's Hospital; Tae Won Kim, The Catholic University of Korea, St. Vincent's Hospital; Yves Dauvilliers, Inserm; Lucie Barateau, Inserm; Gert Jan Lammers, Leids Universitair Medisch Centrum; Rolf Fronczek, Leids Universitair Medisch Centrum; Geert Mayer, Hephata Klinik; Joan Santamaria, Universitat de Barcelona; Isabelle Arnulf, AP-HP Assistance Publique - Hopitaux de Paris; Stine Knudsen-Heier, Oslo Universitetssykehus; May Kristin Lyamouri Bredahl, Oslo Universitetssykehus; Per M Thorsby, Oslo Universitetssykehus; Giuseppe Plazzi, Università degli Studi di Bologna, Facoltà di Medicina e Chirurgia; Fabio Pizza, Università degli Studi di Bologna, Facoltà di Medicina e Chirurgia; Monica Moresco, Università degli Studi di Bologna, Facoltà di Medicina e Chirurgia; Catherine Crowe, Mater Private Hospital Dublin; Stephen K Van den Eeden, Kaiser Permanente Division of Research; Michel Lecendreux, Hôpital Robert-Debré AP-HP; Patrice Bourgin, Les Hôpitaux Universitaires de Strasbourg; Takashi Kanbayashi, Graduate School of Medicine; Francisco J Martínez-Orozco, San Carlos University Hospital. University Complutense of Madrid, Madrid, Spain; Rosa Peraita-Adrados, Hospital General Universitario Gregorio Marañon; Antonio Benetó, Sleep Unit. Medical Center Valencia; Jacques Montplaisir, Hôpital du Sacré-Cœur-de-Montréal; Alex Desautels, Hôpital du Sacré-Cœur-de-Montréal; Yu-Shu Huang, Chang Gung Memorial Hospital; Poul Jennum, University of Copenhagen; Sona Nevsimalova, Charles University and General University Hosptal, Prague, Czech Republic; David Kemlink, Charles University and General University Hosptal, Prague, Czech Republic; Alex Iranzo, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Sebastiaan Overeem, Sleep Medicine Center Kempenhaeghe; Aleksandra Wierzbicka, Institute of Psychiatry and Neurology, Warsaw, Poland; Peter Geisler, University of Regensburg, Regensburg, Germany; Karel Sonka, Charles University and General University Hosptal, Prague, Czech Republic; Makoto Honda, Tokyo Metropolitan Institute of Medical Science; Birgit Högl, Medical University Innsbruck (MUI), Innsbruck, Austria; Ambra Stefani, Medical University Innsbruck (MUI), Innsbruck, Austria; Fernando Morgadinho Coelho, Universidade Federal de São Paulo; Vilma Mantovani, St. Orsola-Malpighi University Hospital; Eva Feketeova, University Hospital of L. Pasteur Kosice; Mia Wadelius, Uppsala University; Niclas Eriksson, Uppsala University; Hans Smedje, Karolinska Institutet, Stockholm, Sweden; Ferini-Strambi Luigi, Università Vita-Salute, Milan, Italy; Claudio L Bassetti, Ospedale Regionale di Lugano, Lugano, Ticino Switzerland; Johannes Mathis, Bern University Hospital; Sheela Nampoothiri, Amrita Institute of Medical Sciences & Research Centre; Ramin Partinen, Bern University Hospital, and University of Bern; Pär Hallberg, Uppsala University; Per Egil Hesla, Coliseum on Majorstua Clinic, Oslo, Norway; David Rye, Emory University; Zerrin Pelin, Hasan Kalyoncu University; Luigi Ferini-Strambi, Università Vita-Salute, Milan, Italy; Claudio L Bassetti, Ospedale Regionale di Lugano, 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, Jerusalem, Israel; Sheela Nampoothiri, Amrita Institute of Medical Sciences & Research Centre, Kerala, India; Tomas Olsson, Karolinska Institutet, Stockholm, Sweden; Ingrid Kockum, Karolinska Institutet, Stockholm, Sweden; Markku Partinen, Helsinki Sleep Clinic, Vitalmed Research Centre, Helsinki, Finland; Markus Perola, University of Tartu; Birgitte R Kornum, University of Copenhagen; Sina Rueger, Swiss Institute of Bioinformatics, Lausanne, Switzerland; Juliane Winkelmann, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Taku Miyagawa, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japa; 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; Kutalik Zoltan, Swiss Institute of Bioinformatics, Lausanne, Switzerland; Ruth O’Hara, Stanford University; Hallmayer Joachim, Stanford University; Chun Jimmie Ye, University of California San Francisco; Emmanuel J Mignot, Stanford University
• Language: English
• Date: 2023-12-01
• Publisher: Springer Nature Limited
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-023-36120-z
• Title of Journal or Parent Work: Nature Communications
• Volume: 14
• Issue: 1
• Start Page: 2709
• End Page: 2709
• Keywords: Influenza Vaccines; Autoimmunity; Influenza, Human; Influenza A Virus, H1N1 Subtype; Autoimmune Diseases; Narcolepsy; Humans
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Mental Health

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®.