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

Nat Commun. 2023 May 15;14(1):2709. doi: 10.1038/s41467-023-36120-z.

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®.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmune Diseases* / epidemiology
  • Autoimmune Diseases* / genetics
  • Autoimmunity / genetics
  • Humans
  • Influenza A Virus, H1N1 Subtype* / genetics
  • Influenza Vaccines* / adverse effects
  • Influenza, Human* / epidemiology
  • Influenza, Human* / genetics
  • Narcolepsy* / chemically induced
  • Narcolepsy* / genetics

Substances

  • Influenza Vaccines