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Summary statistics from a genome-wide association study of narcolepsy

Cite this dataset

Ollila, Hanna et al. (2023). Summary statistics from a genome-wide association study of narcolepsy [Dataset]. Dryad. https://doi.org/10.5061/dryad.kd51c5b9b

Abstract

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 (TRATRBCTSHIFNAR1ZNF365 and P2RY11) and five are new (PRF1CD207SIRPGIL27 and ZFAND2A). Strikingly, in vaccination-related cases, GWA significant effects were found in HLATRA, 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 remarkably 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.

Funding

Academy of Finland, Award: 309643

Wake Up Narcolepsy

Jazz Pharmaceuticals (Ireland)

Donations

National Institutes of Health, Award: NIH-23724

GlaxoSmithKline (United Kingdom)

Sigrid Juselius Foundation

Finnish Cultural Foundation

Orion Farmos Research Foundation

Instrumentarium Science Foundation

Oskar Öfflund Foundation

Yrjö Jahnsson Foundation

Jalmari and Rauha Ahokas Foundation

United States Department of Defense, Award: National Defense Science & Engineering Graduate Fellowship

Stanford University, Award: Graduate Fellowship

National Institute of Mental Health, Award: 5RC2MH089916

Swedish medical product agency

Ministry of Economy, Industry and Competitiveness, Award: 2015CB856405

National Natural Science Foundation of China, Award: 81420108002

National Natural Science Foundation of China, Award: 81670087

Einstein Center for Neurosciences

National Institute of Mental Health, Award: 5RC2MH089916

German Academic Exchange Service