Narcolepsy risk loci are enriched in immune cells and suggest autoimmune modulation of the T cell receptor repertoire
Authors: Ollila Hanna M , Sharon Eilon , Lin Ling , Sinnott-Armstrong Nasa , Ambati Aditya , Hillary Ryan P , Jolanki Otto , Faraco Juliette , Einen Mali , Luo Guo , Zhang Jing , Han Fang , Yan Han , Dong Xiao Song , Li Jing , Zhang Jun , Hong Seung-Chul , Kim Tae Won , Dauvilliers Yves , Barateau Lucie , Lammers Gert Jan , Fronczek Rolf , Mayer Geert , Santamaria Joan , Arnulf Isabelle , Knudsen Stine , Bredahl May Kristin Lyamouri , Thorsby Per Medbøe , Plazzi Giuseppe , Pizza Fabio , Moresco Monica , Crowe Catherine , Van den Eeden Stephen K , Lecendreux Michel , Bourgin Patrice , Kanbayashi Takashi , Peraita-Adrados Rosa , Martínez-Orozco Francisco J , Benetó Antonio , Montplaisir Jacques , Desautels Alex , Huang Yu-Shu , Jennum Poul , Nevsimalova Sona , Kemlink David , Iranzo Alex , Overeem Sebastian , Wierzbicka Aleksandra , Geisler Peter , Sonka Karel , Honda Makoto , Högl Birgit , Stefani Ambra , Coelho Fernando Morgadinho , Mantovani Vilma , Feketeova Eva , Wadelius Mia , Eriksson Niclas , Smedje Hans , Hallberg Pär , Hesla Per Egil , Rye David , Pelin Zerrin , Ferini-Strambi Luigi , Bassetti Claudio L , Mathis Johannes , Khatami Ramin , Aran Adi , Nampoothiri Sheela , Olsson Tomas , Kockum Ingrid , Partinen Markku , Perola Markus , Kornum Birgitte R , Rueger Sina , Winkelmann Juliane , Miyagawa Taku , Toyoda Hiromi , Khor Seik Soon , Shimada Mihoko , Tokunaga Katsushi , Rivas Manuel , Pritchard Jonathan K , Risch Neil , Kutalik Zoltan , O’Hara Ruth , Hallmayer Joachim , Ye Chun Jimmie , Mignot Emmanuel 
Published: July 2018

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.