Journal Article

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

Jolanki, Otto, Dauvilliers, Yves, Pizza, Fabio, Rueger, Sina, Han, Fang, Aran, Adi, Iranzo, Alex, Rye, David, Martínez-Orozco, Francisco J., Moresco, Monica, Eriksson, Niclas, Kockum, Ingrid, Zhang, Jing, Winkelmann, Juliane, Lammers, Gert Jan, Mayer, Geert, Khatami, Ramin, Mignot, Emmanuel J., Hallberg, Pär, Feketeova, Eva, Khor, Seik-Soon, Pritchard, Jonathan K., Kemlink, David, Smedje, Hans, Sonka, Karel, Mathis, Johannes, Jennum, Poul, Bourgin, Patrice, Yogeshwar, Selina M., Hallmayer, Joachim, Barateau, Lucie, Benetó, Antonio, O’Hara, Ruth, Knudsen-Heier, Stine, Lin, Ling, Tokunaga, Katsushi, Hong, Seung-Chul, Overeem, Sebastiaan, Desautels, Alex, Högl, Birgit, Ferini-Strambi, Luigi, Sharon, Eilon, Geisler, Peter, Ollila, Hanna M., Dong, Xiao Song, Faraco, Juliette, Huang, Yu-Shu, Kim, Tae Won, Thorsby, Per Medbøe, Olsson, Tomas, Shimada, Mihoko, Zhang, Jun, Ye, Chun Jimmie, Hesla, Per Egil, Kornum, Birgitte R., Santamaria, Joan, Honda, Makoto, Hillary, Ryan P., Kanbayashi, Takashi, Montplaisir, Jacques, Crowe, Catherine, Yan, Han, Mantovani, Vilma, Nampoothiri, Sheela, Kutalik, Zoltan, Einen, Mali, Van den Ee

2023

Overview

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®. Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/43 / 631/208 / 631/208/205/2138 / 692/4017 / Autoimmune Diseases / Autoimmune Diseases - epidemiology / Autoimmune Diseases - genetics / Autoimmunity / Autoimmunity - genetics / Comorbidity / Environmental risk / ErbB-3 protein / Gene loci / Genetic analysis / Genetic diversity / Genetic variance / Heritability / Human health and pathology / Humanities and Social Sciences / Humans / Immune system / Immunization / Infections / Influenza / Influenza A / Influenza A Virus, H1N1 Subtype / Influenza A Virus, H1N1 Subtype - genetics / Influenza Vaccines / Influenza Vaccines - adverse effects / Influenza, Human / Influenza, Human - epidemiology / Influenza, Human - genetics / Life Sciences / Lymphocytes / Lymphocytes T / multidisciplinary / Narcolepsy / Narcolepsy - chemically induced / Narcolepsy - genetics / Neurotrophin 1 / Orexins / Risk factors / Science / Science (multidisciplinary) / Sleep disorders / T cell receptors / Vaccination / Vaccines