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

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  • Hanna M. Ollila
  • Eilon Sharon
  • Ling Lin
  • Nasa Sinnott-Armstrong
  • Aditya Ambati
  • Selina M. Yogeshwar
  • Ryan P. Hillary
  • Otto Jolanki
  • Juliette Faraco
  • Mali Einen
  • Guo Luo
  • Jing Zhang
  • Fang Han
  • Han Yan
  • Xiao Song Dong
  • Jing Li
  • Jun Zhang
  • Seung Chul Hong
  • Tae Won Kim
  • Yves Dauvilliers
  • Lucie Barateau
  • Gert Jan Lammers
  • Rolf Fronczek
  • Geert Mayer
  • Joan Santamaria
  • Isabelle Arnulf
  • Stine Knudsen-Heier
  • May Kristin Lyamouri Bredahl
  • Per Medbøe Thorsby
  • Giuseppe Plazzi
  • Fabio Pizza
  • Monica Moresco
  • Catherine Crowe
  • Stephen K. Van den Eeden
  • Michel Lecendreux
  • Patrice Bourgin
  • Takashi Kanbayashi
  • Francisco J. Martínez-Orozco
  • Rosa Peraita-Adrados
  • Antonio Benetó
  • Jacques Montplaisir
  • Alex Desautels
  • Yu Shu Huang
  • Jennum, Poul
  • Sona Nevsimalova
  • David Kemlink
  • Alex Iranzo
  • Sebastiaan Overeem
  • Aleksandra Wierzbicka
  • Kornum, Birgitte Rahbek (Member of author collaboration)
  • FinnGen

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®.

Original languageEnglish
Article number2709
JournalNature Communications
Issue number1
Number of pages13
Publication statusPublished - 2023

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© 2023. The Author(s).

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