학술논문
Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy
Document Type
article
Author
Ollila, Hanna M; Sharon, Eilon; Lin, Ling; Sinnott-Armstrong, Nasa; Ambati, Aditya; Yogeshwar, Selina M; 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-Heier, 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; Martínez-Orozco, Francisco J; Peraita-Adrados, Rosa; Benetó, Antonio; Montplaisir, Jacques; Desautels, Alex; Huang, Yu-Shu; Jennum, Poul; Nevsimalova, Sona; Kemlink, David; Iranzo, Alex; Overeem, Sebastiaan; 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 J
Source
Nature Communications. 14(1)
Subject
Language
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®.