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 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 Santamaría, Isabelle Arnulf, Stine Knudsen, 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, F Martínez-Orozco, Rosa Peraita‐Adrados, Antonio Benetó, Jacques Montplaisir, Alex Désautels, Yu‐Shu Huang, FinnGen, Thomas D. Als, Adam Ziemann, Ali Abbasi, Anne Lehtonen, Apinya Lertratanakul, Bridget Riley‐Gillis, Fedik Rahimov, Howard J. Jacob, Jeffrey F. Waring, Mengzhen Liu, Nizar Smaoui, Relja Popovic, Adam Platt, Athena Matakidou, Benjamin Challis, Dirk S. Paul, Glenda Lassi, Ioanna Tachmazidou, Antti Hakanen, Johanna Schleutker, Nina Pitkänen, Perttu Terho, Petri Virolainen, Arto Mannermaa, Veli‐Matti Kosma, Chia‐Yen Chen, Heiko Runz, Sally John, Sanni Lahdenperä, Stephanie Loomis, Susan Eaton, George Okafo, Heli Salminen‐Mankonen, Marc Jung, Nathan Lawless, Zhihao Ding, Joseph Maranville, Marla Hochfeld, Robert M. Plenge, Shameek Biswas, Masahiro Kanai, Mutaamba Maasha, Wei Zhou, Outi Tuovila, Raimo Pakkanen, Jari A. Laukkanen, Teijo Kuopio, Kristiina Aittomäki, Antti Mäkitie, Natalia Pujol, Triin Laisk, Katriina Aalto‐Setälä, Johanna Mäkelä, Marco Hautalahti, Sarah Smith, Tom Southerington
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®.