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Narcolepsy risk loci are enriched in immune cells and suggest autoimmune modulation of the T cell receptor repertoire

By Hanna Ollila, Eilon Sharon, Ling Lin, Nasa Sinnott-Armstrong, Aditya Ambati, Ryan P Hillary, Otto Jolanki, Juliette Faraco, Mali Einen, Guo Luo, Jing Zhang, Fang Han, Han Yan, Xiao Song Dong, Jing Li, Seung-Chul Hong, Tae Won Kim, Yves Dauvilliers, Lucie Barateau, Gert Jan Lammers, Rolf Fronczek, Geert Mayer, Joan Santamaria, Isabelle Arnulf, Stine Knudsen, May Kristin Lyamouri-Bredahl, Per Medboe Thorsby, Giuseppe Plazzi, Fabio Pizza, Monica Moresco, Catherine Crowe, Stephen K Van-den-Eeden, Michel Lecendreux, Patrice Bourgin, Takashi Kanbayashi, Rosa Peraita-Adrados, Francisco J Martinez-Orozco, Antonio Beneto, Jacques Montplaisir, Akex Desautels, Yu-Shu Huang, Poul Jennum, Sona Nevsimalova, David Kemlink, Alex Iranzo, Sebastian Overeem, Aleksandra Wierzbicka, Peter Geisler, Karel Sonka, Makoto Honda, Birgit Hogl, Birgit Frauscher, Ambra Stefani, Fernando Morgadinho Coelho, Vilma Mantovani, Eva Feketeova, Mia Wadelius, Niclas Eriksson, Hans Smedje, Par 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 OHara, Joachim Hallmayer, Jimmie Ye, Emmanuel Mignot

Posted 22 Jul 2018
bioRxiv DOI: 10.1101/373555

Type 1 narcolepsy (T1N) is a neurological condition, in which the death of hypocretin-producing neurons in the lateral hypothalamus leads to excessive daytime sleepiness and symptoms of abnormal Rapid Eye Movement (REM) sleep. Known triggers for narcolepsy are influenza-A infection and associated immunization during the 2009 H1N1 influenza pandemic. Here, we genotyped all remaining consented narcolepsy cases worldwide and assembled this with the existing genotyped individuals. We used this multi-ethnic sample in genome wide association study (GWAS) to dissect disease mechanisms and interactions with environmental triggers (5,339 cases and 20,518 controls). Overall, we found significant associations with HLA (2 GWA significant subloci) and 11 other loci. Six of these other loci have been previously reported (TRA, TRB, CTSH, IFNAR1, ZNF365 and P2RY11) and five are new (PRF1, CD207, SIRPG, IL27 and ZFAND2A). Strikingly, in vaccination-related cases GWA significant effects were found in HLA, TRA, and in a novel variant near SIRPB1. Furthermore, IFNAR1 associated polymorphisms regulated dendritic cell response to influenza-A infection in vitro (p-value =1.92*10-25). A partitioned heritability analysis indicated specific enrichment of functional elements active in cytotoxic and helper T cells. Furthermore, functional analysis showed the genetic variants in TRA and TRB loci act as remarkable strong chain usage QTLs for TRAJ*24 (p-value = 0.0017), TRAJ*28 (p-value = 1.36*10-10) and TRBV*4-2 (p-value = 3.71*10-117). This was further validated in TCR sequencing of 60 narcolepsy cases and 60 DQB1*06:02 positive controls, where chain usage effects were further accentuated. Together these findings show that the autoimmune component in narcolepsy is defined by antigen presentation, mediated through specific T cell receptor chains, and modulated by influenza-A as a critical trigger.

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