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

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  • Hanna M. Ollila

    (Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences
    University of Helsinki
    Massachusetts General Hospital and Harvard Medical School
    Center for Genomic Medicine, Massachusetts General Hospital)

  • Eilon Sharon

    (Stanford University
    Stanford University)

  • Ling Lin

    (Stanford University, Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences)

  • Nasa Sinnott-Armstrong

    (Stanford University
    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
    Charité–Universitätsmedizin
    Charité—Universitätsmedizin Berlin, Einstein Center for Neurosciences Berlin)

  • 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
    Stichting Epilepsie Instellingen Nederland (SEIN), Sleep-Wake Centre)

  • Rolf Fronczek

    (Leiden University Medical Center
    Stichting Epilepsie Instellingen Nederland (SEIN), Sleep-Wake Centre)

  • Geert Mayer

    (Hephata Klinik
    Philipps Universität Marburg)

  • 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
    Oslo University Hospital)

  • Per Medbøe Thorsby

    (Oslo University Hospital)

  • Giuseppe Plazzi

    (University of Bologna
    IRCCS Institute of Neurological Sciences)

  • Fabio Pizza

    (University of Bologna
    IRCCS Institute of Neurological Sciences)

  • Monica Moresco

    (University of Bologna
    IRCCS Institute of Neurological Sciences)

  • 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
    University of Tsukuba)

  • 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)
    Department of Neurology
    Multidisciplinary Sleep Disorders Unit)

  • Sebastiaan Overeem

    (Sleep Medicine Center Kempenhaeghe
    Eindhoven University of Technology)

  • 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
    Seiwa Hospital, Neuropsychiatric Research Institute)

  • 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
    Uppsala Clinical Research Center)

  • 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
    Bern University Hospital, and University of Bern)

  • Johannes Mathis

    (Bern University Hospital, and University of Bern)

  • Ramin Khatami

    (Bern University Hospital, and University of Bern
    Center for Sleep Medicine and Sleep Research, Clinic Barmelweid AG)

  • 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
    University of Helsinki)

  • 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
    Munich Cluster for Systems Neurology (SyNergy)
    Neurologische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München)

  • Taku Miyagawa

    (Tokyo Metropolitan Institute of Medical Science
    The University of Tokyo)

  • 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
    University Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland)

  • Ruth O’Hara

    (Stanford University
    Mental Illness Research Education Clinical Centers (MIRECC), VA Palo Alto)

  • Joachim Hallmayer

    (Stanford University
    Mental Illness Research Education Clinical Centers (MIRECC), VA Palo Alto)

  • 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)

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®.

Suggested Citation

  • 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 H, 2023. "Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36120-z
    DOI: 10.1038/s41467-023-36120-z
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    as
    1. Daniela Latorre & Ulf Kallweit & Eric Armentani & Mathilde Foglierini & Federico Mele & Antonino Cassotta & Sandra Jovic & David Jarrossay & Johannes Mathis & Francesco Zellini & Burkhard Becher & Ant, 2018. "T cells in patients with narcolepsy target self-antigens of hypocretin neurons," Nature, Nature, vol. 562(7725), pages 63-68, October.
    2. Natasja Wulff Pedersen & Anja Holm & Nikolaj Pagh Kristensen & Anne-Mette Bjerregaard & Amalie Kai Bentzen & Andrea Marion Marquard & Tripti Tamhane & Kristoffer Sølvsten Burgdorf & Henrik Ullum & Pou, 2019. "CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    3. Wei Jiang & James R. Birtley & Shu-Chen Hung & Weiqi Wang & Shin-Heng Chiou & Claudia Macaubas & Birgitte Kornum & Lu Tian & Huang Huang & Lital Adler & Grant Weaver & Liying Lu & Alexandra Ilstad-Min, 2019. "In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
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