Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy
Hanna M. Ollila(University of Helsinki), Eilon Sharon(Stanford University), Ling Lin(Stanford University), Nasa Sinnott-Armstrong(Stanford University), Aditya Ambati(Stanford University), Selina Yogeshwar(Einstein Center for Neurosciences Berlin), Ryan P. Hillary(Stanford University), Otto Jolanki(Stanford University), Juliette Faraco(Stanford University), Mali Einen(Stanford University), Guo Luo(Stanford University), Jing Zhang(Peking University), Fang Han(Peking University), Han Yan(Peking University), Xiao Song Dong(Peking University), Jing Li(Peking University), Jun Zhang(Peking University), 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(Leiden University Medical Center), Rolf Fronczek(Leiden University Medical Center), Geert Mayer(Philipps University of Marburg), Joan Santamaría(Universitat de Barcelona), Isabelle Arnulf(Sorbonne Université), Stine Knudsen(Oslo University Hospital), May Kristin Lyamouri Bredahl(Oslo University Hospital), Per Medbøe Thorsby(Oslo University Hospital), Giuseppe Plazzi(Institute of Neurological Sciences), Fabio Pizza(Institute of Neurological Sciences), Monica Moresco(Institute of Neurological Sciences), Catherine Crowe(Mater Misericordiae University Hospital), Stephen K. Van Den Eeden(Kaiser Permanente), Michel Lecendreux, Patrice Bourgin(Université de Strasbourg), Takashi Kanbayashi(University of Tsukuba), F Martínez-Orozco(Hospital Clínico San Carlos), Rosa Peraita‐Adrados(Hospital General Universitario Gregorio Marañón), Antonio Benetó, Jacques Montplaisir(Hôpital du Sacré-Cœur de Montréal), Alex Désautels(Hôpital du Sacré-Cœur de Montréal), Yu‐Shu Huang(Chang Gung Memorial Hospital), FinnGen(Aarhus University), Thomas D. Als(Aarhus University), Adam Ziemann(AbbVie (United States)), Ali Abbasi(AbbVie (United States)), Anne Lehtonen(AbbVie (United States)), Apinya Lertratanakul(AbbVie (United States)), Bridget Riley‐Gillis(AbbVie (United States)), Fedik Rahimov(AbbVie (United States)), Howard J. Jacob(AbbVie (United States)), Jeffrey F. Waring(AbbVie (United States)), Mengzhen Liu(AbbVie (United States)), Nizar Smaoui(AbbVie (United States)), Relja Popovic(AstraZeneca (United Kingdom)), Adam Platt(AstraZeneca (United Kingdom)), Athena Matakidou(AstraZeneca (United Kingdom)), Benjamin Challis(AstraZeneca (United Kingdom)), Dirk S. Paul(AstraZeneca (United Kingdom)), Glenda Lassi(AstraZeneca (United Kingdom)), Ioanna Tachmazidou(AstraZeneca (United Kingdom)), Antti Hakanen(University of Turku), Johanna Schleutker(University of Turku), Nina Pitkänen(University of Turku), Perttu Terho(University of Turku), Petri Virolainen(University of Turku), Arto Mannermaa(University of Eastern Finland), Veli‐Matti Kosma(Biogen (United States)), Chia‐Yen Chen(Biogen (United States)), Heiko Runz(Biogen (United States)), Sally John(Biogen (United States)), Sanni Lahdenperä(Biogen (United States)), Stephanie Loomis(Biogen (United States)), Susan Eaton(Biogen (United States)), George Okafo(Boehringer Ingelheim (Germany)), Heli Salminen‐Mankonen(Boehringer Ingelheim (Germany)), Marc Jung(Boehringer Ingelheim (Germany)), Nathan Lawless(Boehringer Ingelheim (Germany)), Zhihao Ding(Boehringer Ingelheim (Germany)), Joseph Maranville(Bristol-Myers Squibb (United States)), Marla Hochfeld(Boehringer Ingelheim (Germany)), Robert M. Plenge(Boehringer Ingelheim (Germany)), Shameek Biswas(Broad Institute), Masahiro Kanai(Broad Institute), Mutaamba Maasha(Broad Institute), Wei Zhou(Broad Institute), Outi Tuovila(Business Finland), Raimo Pakkanen(Central Finland Health Care District), Jari A. Laukkanen(Central Finland Health Care District), Teijo Kuopio(Helsinki University Hospital), Kristiina Aittomäki(University of Helsinki), Antti Mäkitie(University of Helsinki), Natalia Pujol, Triin Laisk(Tampere University), Katriina Aalto‐Setälä(Tampere University), Johanna Mäkelä, Marco Hautalahti, Sarah Smith, Tom Southerington(Tampere University), Eeva Kangasniemi(Tampere University), Henna Palin(Tampere University), Mika Kähönen(Tampere University), Sanna Siltanen(Tampere University), Tarja Laitinen(Tampere University), Felix Vaura(Finnish Institute for Health and Welfare), Jaana Suvisaari(Finnish Institute for Health and Welfare), Teemu Niiranen(Finnish Institute for Health and Welfare), Veikko Salomaa(Finnish Red Cross), Jukka Partanen(University of Helsinki), Mikko Arvas(Finnish Red Cross), Jarmo Ritari(Finnish Red Cross), Kati Hyvärinen(Finnish Red Cross), David F. Choy, Edmond Teng, Erich C. Strauss, Hao Chen, Hubert Chen, Jennifer L. Schutzman, Julie Hunkapiller, Mark I. McCarthy, Natalie Bowers, Rion Pendergrass, Tim Lu(GlaxoSmithKline (United Kingdom)), Audrey Y. Chu(GlaxoSmithKline (United Kingdom)), Diptee Kulkarni(GlaxoSmithKline (United Kingdom)), Fanli Xu(GlaxoSmithKline (United Kingdom)), Joanna Betts(GlaxoSmithKline (United Kingdom)), John D. Eicher(GlaxoSmithKline (United Kingdom)), Jorge Esparza Gordillo(GlaxoSmithKline (United Kingdom)), Laura Addis(GlaxoSmithKline (United Kingdom)), Linda McCarthy(GlaxoSmithKline (United Kingdom)), Rajashree Mishra(GlaxoSmithKline (United Kingdom)), Janet Kumar(GlaxoSmithKline (United States)), Margaret G. Ehm(GlaxoSmithKline (United States)), Kirsi Auro(GlaxoSmithKline (United Kingdom)), David Pulford(GlaxoSmithKline (United Kingdom)), Anne Pitkäranta(Hospital District of Helsinki and Uusimaa), Anu Loukola(Hospital District of Helsinki and Uusimaa), Eero Punkka(Hospital District of Helsinki and Uusimaa), Malla-Maria Linna(Hospital District of Helsinki and Uusimaa), Olli Carpén(Hospital District of Helsinki and Uusimaa), Taneli Raivio(University of Helsinki), Joni A. Turunen(University of Helsinki), Tomi P. Mäkelä(University of Helsinki), Aino Salminen(Hospital District of Helsinki and Uusimaa), Antti A. Aarnisalo(Hospital District of Helsinki and Uusimaa), Daniel Gordin(Hospital District of Helsinki and Uusimaa), David Rice(Hospital District of Helsinki and Uusimaa), Erkki Isometsä(Hospital District of Helsinki and Uusimaa), Eveliina Salminen(Hospital District of Helsinki and Uusimaa), Heikki Joensuu(Hospital District of Helsinki and Uusimaa), Ilkka Kalliala(Hospital District of Helsinki and Uusimaa), Johanna Mattson(Hospital District of Helsinki and Uusimaa), Juha Sinisalo(Hospital District of Helsinki and Uusimaa), Jukka Koskela(Hospital District of Helsinki and Uusimaa), Kari K. Eklund(Hospital District of Helsinki and Uusimaa), Katariina Hannula‐Jouppi(Hospital District of Helsinki and Uusimaa), Lauri A. Aaltonen(Hospital District of Helsinki and Uusimaa), Marja‐Riitta Taskinen(Hospital District of Helsinki and Uusimaa), Martti Färkkilâ(Hospital District of Helsinki and Uusimaa), Minna Raivio(Hospital District of Helsinki and Uusimaa), Oskari Heikinheimo(Hospital District of Helsinki and Uusimaa), Paula Kauppi(Hospital District of Helsinki and Uusimaa), Pekka Nieminen(Hospital District of Helsinki and Uusimaa), Pentti Tienari(Hospital District of Helsinki and Uusimaa), Pirkko J. Pussinen(Hospital District of Helsinki and Uusimaa), Sampsa Pikkarainen(Hospital District of Helsinki and Uusimaa), Terhi Ollila(Hospital District of Helsinki and Uusimaa), Tiinamaija Tuomi(Hospital District of Helsinki and Uusimaa), Timo P. Hiltunen(Hospital District of Helsinki and Uusimaa), Tuomo J Meretoja(Hospital District of Helsinki and Uusimaa), Tuula Salo(Hospital District of Helsinki and Uusimaa), Ulla Palotie(Varsinais-Suomen Sairaanhoitopiiri), Antti Palomäki(Varsinais-Suomen Sairaanhoitopiiri), Jenni Aittokallio(Varsinais-Suomen Sairaanhoitopiiri), Juha O. Rinne(Varsinais-Suomen Sairaanhoitopiiri), Kaj Metsärinne(Varsinais-Suomen Sairaanhoitopiiri), Klaus Elenius(Varsinais-Suomen Sairaanhoitopiiri), Laura Pirilä(Varsinais-Suomen Sairaanhoitopiiri), Leena Koulu(Varsinais-Suomen Sairaanhoitopiiri), Markku Voutilainen(Varsinais-Suomen Sairaanhoitopiiri), Riitta Lahesmaa(Varsinais-Suomen Sairaanhoitopiiri), Roosa Kallionpää(Varsinais-Suomen Sairaanhoitopiiri), Sirkku Peltonen(Varsinais-Suomen Sairaanhoitopiiri), Tytti Willberg(Varsinais-Suomen Sairaanhoitopiiri), Ulvi Kahraman Gürsoy(Varsinais-Suomen Sairaanhoitopiiri), Varpu Jokimaa(University of Helsinki), Aarno Palotie(University of Helsinki), Anastasia Kytölä(University of Helsinki), Andrea Ganna(University of Helsinki), Anu Jalanko(University of Helsinki), Aoxing Liu(University of Helsinki), Arto Lehistö(University of Helsinki), Awaisa Ghazal(University of Helsinki), Elina Kilpeläinen(University of Helsinki), Elisabeth Widén(University of Helsinki), Elmo Saarentaus(University of Helsinki), Esa Pitkänen(University of Helsinki), Hanna M. Ollila(University of Helsinki), Hannele Laivuori(University of Helsinki), Henrike Heyne(University of Helsinki), Huei-Yi Shen(University of Helsinki), Jaakko Kaprio(University of Helsinki), Joel Rämö(University of Helsinki), Juha Karjalainen(University of Helsinki), Juha Mehtonen(University of Helsinki), Jyrki Pitkänen(University of Helsinki), Kalle Pärn(University of Helsinki), Kati Donner(University of Helsinki), Katja Kivinen(University of Helsinki), L. Elisa Lahtela(University of Helsinki), Mari Niemi(University of Helsinki), Mari Kaunisto(University of Helsinki), Mart Kals(University of Helsinki), Mary Pat Reeve(University of Helsinki), Mervi Aavikko(University of Helsinki), Nina Mars(University of Helsinki), Oluwaseun Alexander Dada(University of Helsinki), Pietro Della Briotta Parolo(University of Helsinki), Priit Palta(University of Helsinki), Rigbe Weldatsadik(University of Helsinki), Risto Kajanne(University of Helsinki), Rodos Rodosthenous(University of Helsinki), Samuli Ripatti(University of Helsinki), Sanni Ruotsalainen(University of Helsinki), Satu Strausz(University of Helsinki), Shabbeer Hassan(University of Helsinki), Shanmukha Sampath Padmanabhuni(University of Helsinki), Shuang Luo(University of Helsinki), Susanna Lemmelä(University of Helsinki), Taru Tukiainen(University of Helsinki), Timo P. Sipilä(University of Helsinki), Tuomo Kiiskinen(University of Helsinki), Vincent Llorens(University of Helsinki), Mark J. Daly(Broad Institute), Jiwoo Lee(Broad Institute), Kristin Tsuo(Broad Institute), Mitja Kurki(Broad Institute), Amanda Elliott(Broad Institute), Aki S. Havulinna(University of Helsinki), Juulia Partanen(University of Helsinki), Robert Yang(Janssen (Belgium)), Dermot F. Reilly(Janssen (United States)), Alessandro Porello(Janssen (United States)), Amy Hart(Janssen (United States)), Dawn Waterworth(Janssen (United States)), Ekaterina Khramtsova(Janssen (United States)), Karen He(Janssen (United States)), Meijian Guan(Janssen (United States)), Qingqin S. Li(Janssen (United States)), Sauli Vuoti(Maze (United States)), Eric Green(Maze (United States)), Robert Graham(Maze (United States)), Sahar V. Mozaffari(Merck & Co., Inc., Rahway, NJ, USA (United States)), Adriana Huertas‐Vázquez(Merck & Co., Inc., Rahway, NJ, USA (United States)), Andrey Loboda(Merck & Co., Inc., Rahway, NJ, USA (United States)), Caroline S. Fox(Merck & Co., Inc., Rahway, NJ, USA (United States)), Fabiana Farias(Merck & Co., Inc., Rahway, NJ, USA (United States)), Jae-Hoon Sul(Merck & Co., Inc., Rahway, NJ, USA (United States)), Jason Miller(Merck & Co., Inc., Rahway, NJ, USA (United States)), Neha Raghavan(Merck & Co., Inc., Rahway, NJ, USA (United States)), Simonne Longerich(Merck & Co., Inc., Rahway, NJ, USA (United States)), Johannes Kettunen(Borealis (Finland)), Raisa Serpi(Borealis (Finland)), Reetta Hinttala(Borealis (Finland)), Tuomo Mantere(Borealis (Finland)), Anne M. Remes(Northern Ostrobothnia Hospital District), Elisa Rahikkala(Northern Ostrobothnia Hospital District), Johanna Huhtakangas(Northern Ostrobothnia Hospital District), Kaisa Tasanen(Northern Ostrobothnia Hospital District), Laura Huilaja(Northern Ostrobothnia Hospital District), Laure Morin‐Papunen(Northern Ostrobothnia Hospital District), Maarit Niinimäki(Northern Ostrobothnia Hospital District), Marja Vääräsmäki(Northern Ostrobothnia Hospital District), Outi Uimari(Northern Ostrobothnia Hospital District), Peeter Karihtala(Northern Ostrobothnia Hospital District), Terhi Piltonen(Northern Ostrobothnia Hospital District), Terttu Harju(Northern Ostrobothnia Hospital District), Timo Blomster(Northern Ostrobothnia Hospital District), Vuokko Anttonen(Northern Ostrobothnia Hospital District), Hilkka Soininen, Kai Kaarniranta, Liisa Suominen, Margit Pelkonen, Maria Siponen, Mikko Kiviniemi, Oili Kaipiainen‐Seppänen, Päivi Auvinen, Päivi Mäntylä, Reetta Kälviäinen, Valtteri Julkunen(Novartis (United States)), Chris O’Donnell(Novartis (United States)), Ma ́en Obeidat(Novartis (United States)), Nicole Renaud(Novartis (Switzerland)), Debby Ngo(Novartis (Switzerland)), Majd Mouded(Novartis (Switzerland)), Mike Mendelson(Pfizer (United States)), Anders Mälarstig(Pfizer (United States)), Heli Lehtonen(Pfizer (United States)), Jaakko Parkkinen(Pfizer (United States)), Kirsi Kalpala(Pfizer (United States)), Melissa Miller(Pfizer (United States)), Nan Bing(Pfizer (United States)), Stefan McDonough(Pfizer (United States)), Xinli Hu(Pfizer (United States)), Ying Wu(Pfizer (United States)), Airi Jussila(Pirkanmaa Hospital District), Annika Auranen(Pirkanmaa Hospital District), Argyro Bizaki-Vallaskangas(Pirkanmaa Hospital District), Hannu Uusitalo(Pirkanmaa Hospital District), Jukka Peltola(Pirkanmaa Hospital District), Jussi Hernesniemi(Pirkanmaa Hospital District), Katri Kaukinen(Pirkanmaa Hospital District), Laura Kotaniemi‐Talonen(Pirkanmaa Hospital District), Pia Isomäki(Pirkanmaa Hospital District), Teea Salmi(Pirkanmaa Hospital District), Venla Kurra(Oulu University Hospital), Kirsi Sipilä(Oulu University Hospital), Auli Toivola(Finnish Institute for Health and Welfare), Elina Järvensivu(Finnish Institute for Health and Welfare), Essi Kaiharju(Finnish Institute for Health and Welfare), Hannele Mattsson(Finnish Institute for Health and Welfare), Kati Kristiansson(Finnish Institute for Health and Welfare), Lotta Männikkö(Finnish Institute for Health and Welfare), Markku Laukkanen(Finnish Institute for Health and Welfare), Markus Perola(Finnish Institute for Health and Welfare), Minna Brunfeldt(Finnish Institute for Health and Welfare), Päivi Laiho(Finnish Institute for Health and Welfare), Regis Wong(Finnish Institute for Health and Welfare), Sami Koskelainen(Finnish Institute for Health and Welfare), Sini Lähteenmäki(Finnish Institute for Health and Welfare), Sirpa Soini(Finnish Institute for Health and Welfare), Teemu Paajanen(Finnish Institute for Health and Welfare), Terhi Kilpi(Finnish Institute for Health and Welfare), Tero Hiekkalinna(Finnish Institute for Health and Welfare), Tuuli Sistonen(Finnish Institute for Health and Welfare), Clément Chatelain, Deepak Raipal, K. Klinger, Samuel Lessard(University of Helsinki), Fredrik Åberg(University of Helsinki), Mikko Hiltunen(University of Eastern Finland), Sami Heikkinen(Tampere University), Hannu Kankaanranta(University of Helsinki), Tuula Palotie(University of Helsinki), Iiris Hovatta(University of Helsinki), Kimmo Palin(University of Helsinki), Niko Välimäki(University of Helsinki), Sanna Toppila‐Salmi(University of Helsinki), Eija K. Laakkonen(University of Jyväskylä), Eeva Sliz(University of Oulu), Heidi Silven(University of Oulu), Katri Pylkäs(University of Oulu), Minna K. Karjalainen(University of Oulu), Riikka K. Arffman(University of Oulu), Susanna Savukoski(University of Oulu), Jaakko Tyrmi(Tampere University), Manuel Rivas(Tampere University), Harri Siirtola(Tampere University), Iida Vähätalo(Tampere University), Javier Gracia‐Tabuenca(Tampere University), Marianna Niemi(University of Helsinki), Mika Helminen(Tampere University), Tiina Luukkaala(University of Copenhagen), Poul Jennum(University of Copenhagen), Soňa Nevšímalová(Charles University), David Kemlink(Charles University), Álex Iranzo(Kempenhaeghe), Sebastiaan Overeem(Kempenhaeghe), Aleksandra Wierzbicka(Institute of Psychiatry and Neurology), Peter Geisler(Charles University), Karel Šonka(Charles University), Makoto Honda(Innsbruck Medical University), Birgit Högl(Innsbruck Medical University), Ambra Stefani(Innsbruck Medical University), Fernando Morgadinho Santos Coelho(IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola), Vilma Mantovani(University of Pavol Jozef Šafárik), Eva Feketeová(Uppsala University), Mia Wadelius(Uppsala University), Niclas Eriksson(Uppsala University), Hans Smedje(Uppsala University), Pär Hallberg(Uppsala University), Per Egil Hesla(Emory University), David B. Rye(Emory University), Zerrin Pelin(IRCCS Ospedale San Raffaele), Luigi Ferini‐Strambi(University of Bern), Claudio L. Bassetti(University of Bern), Johannes Mathis(University of Bern), Ramin Khatami(University of Bern), Adi Aran(Amrita Institute of Medical Sciences and Research Centre), Sheela Nampoothiri(Amrita Institute of Medical Sciences and Research Centre), Tomas Olsson(Karolinska Institutet), Ingrid Kockum(University of Helsinki), Markku Partinen(University of Helsinki), Markus Perola(University of Copenhagen), Birgitte Rahbek Kornum(University of Copenhagen), Sina Rüeger(SIB Swiss Institute of Bioinformatics), Juliane Winkelmann(TUM Klinikum), 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(Palo Alto University), Manuel Rivas(Palo Alto University), Jonathan K. Pritchard(Stanford University), Neil Risch(University of Lausanne), Zoltán Kutalik(SIB Swiss Institute of Bioinformatics), Ruth O’Hara(Mental Illness Research, Education and Clinical Centers), Joachim Hallmayer(University of California, San Francisco), Chun Ye(University of California, San Francisco), Emmanuel Mignot(Stanford Medicine)
Cited by 59Open Access
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®.
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