RT Journal Article
SR Electronic
T1 Narcolepsy risk loci are enriched in immune cells and suggest autoimmune modulation of the T cell receptor repertoire
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 373555
DO 10.1101/373555
A1 Hanna M Ollila
A1 Eilon Sharon
A1 Ling Lin
A1 Nasa Sinnott-Armstrong
A1 Aditya Ambati
A1 Ryan P Hillary
A1 Otto Jolanki
A1 Juliette Faraco
A1 Mali Einen
A1 Guo Luo
A1 Jing Zhang
A1 Fang Han
A1 Han Yan
A1 Xiao Song Dong
A1 Jing Li
A1 Jun Zhang
A1 Seung-Chul Hong
A1 Tae Won Kim
A1 Yves Dauvilliers
A1 Lucie Barateau
A1 Gert Jan Lammers
A1 Rolf Fronczek
A1 Geert Mayer
A1 Joan Santamaria
A1 Isabelle Arnulf
A1 Stine Knudsen
A1 May Kristin Lyamouri Bredahl
A1 Per Medbøe Thorsby
A1 Giuseppe Plazzi
A1 Fabio Pizza
A1 Monica Moresco
A1 Catherine Crowe
A1 Stephen K Van den Eeden
A1 Michel Lecendreux
A1 Patrice Bourgin
A1 Takashi Kanbayashi
A1 Rosa Peraita-Adrados
A1 Francisco J Martínez-Orozco
A1 Antonio Benetó
A1 Jacques Montplaisir
A1 Alex Desautels
A1 Yu-Shu Huang
A1 Poul Jennum
A1 Sona Nevsimalova
A1 David Kemlink
A1 Alex Iranzo
A1 Sebastian Overeem
A1 Aleksandra Wierzbicka
A1 Peter Geisler
A1 Karel Sonka
A1 Makoto Honda
A1 Birgit Högl
A1 Ambra Stefani
A1 Fernando Morgadinho Coelho
A1 Vilma Mantovani
A1 Eva Feketeova
A1 Mia Wadelius
A1 Niclas Eriksson
A1 Hans Smedje
A1 Pär Hallberg
A1 Per Egil Hesla
A1 David Rye
A1 Zerrin Pelin
A1 Luigi Ferini-Strambi
A1 Claudio L Bassetti
A1 Johannes Mathis
A1 Ramin Khatami
A1 Adi Aran
A1 Sheela Nampoothiri
A1 Tomas Olsson
A1 Ingrid Kockum
A1 Markku Partinen
A1 Markus Perola
A1 Birgitte R Kornum
A1 Sina Rueger
A1 Juliane Winkelmann
A1 Taku Miyagawa
A1 Hiromi Toyoda
A1 Seik Soon Khor
A1 Mihoko Shimada
A1 Katsushi Tokunaga
A1 Manuel Rivas
A1 Jonathan K Pritchard
A1 Neil Risch
A1 Zoltan Kutalik
A1 Ruth O’Hara
A1 Joachim Hallmayer
A1 Chun Jimmie Ye
A1 Emmanuel Mignot
YR 2018
UL http://biorxiv.org/content/early/2018/07/22/373555.abstract
AB 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.