HLA-DQB1*03:01 strongly affects age of onset of type 1 narcolepsy independently of DQA1 and ethnicity

Abstract In this study, we investigated the effects of HLA-DQB1*03:01 on the onset age of type-1 narcolepsy. We pooled data from 5,339 cases from China, Europe, Korea, Japan, and the United States to conduct the first transethnic study on age of onset (OA). GWAS was used to detect the associated genes. HLA alleles were imputed by HIBAG. Three datasets (DGN, CHINA, and CAUC) were used for TCR analyses. Chinese patients were found to have an earlier age of onset. Independently of this, only one strong GWAS significant effect was observed, summarized by the presence of DQB1*03:01 and centered around the coding region of this gene. In contrast, DQ0602 dosage did not strongly affect onset, and other known narcolepsy-associated genetic loci had minor effects. The DQB1*03:01 effect (mean −3.47 years, p=1.7 10-18) showed no heterogeneity across ethnic groups and was independent of common allelic variation at DQA1 in cis of DQB1*03:01 (DQA1*03:03; DQA1*0505; DQA1*06:01). This effect may be explained by presentation of peptide(s) across all DQ0301 heterodimers, or, considering genetic effects mapping on TCRA and TCRB, effects on TCR repertoire. Using bulk and single-cell RNA-seq data across two ethnic groups, we found that DQB1*03:01 alters TCR repertoire at specific positions, most significantly within the CDR2A, CDR2B and CDR3B loops. These results illustrate the remarkable conservation of narcolepsy genetic effects across ethnicity and suggest that specific TCRs regulate narcolepsy onset. This result will likely be illuminating of the pathophysiology once T cells causative of the disease have been identified. Competing Interest Statement The authors have declared no competing interest. Funding Statement Study funded by a grant from Wake Up Narcolepsy. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was obtained by local Institutional Review Boards (IRB) of collaborating institutions and by Stanford IRB. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors