HLA-DQB1*03:01 strongly affects age of onset of type 1 narcolepsy independently of DQA1 and ethnicity
Abstract
Type 1 narcolepsy (T1N), an autoimmune disease associated with a disruption of hypocretin/orexin neurons, has conserved genetic effects transcending cultures and ethnicities. We pooled data from 5,339 cases from China, Europe, Korea, Japan, and the United States to conduct the first transethnic genome-wide association study (GWAS) on age of onset. Only one strong GWAS significant effect was observed across all ethnicities, summarized by the presence of human leukocyte antigen (HLA)-DQB1*03:01, and centered around the coding region of this gene. In contrast, HLA-DQB1*06:02-positive heterodimer (DQ0602) dosage did not strongly affect onset, and other known narcolepsy-associated genetic loci had minor effects. The HLA-DQB1*03:01 effect (mean −3.47 y, P = 1.7 × 10 −18 ) showed no heterogeneity across ethnic groups and was independent of common allelic variation at HLA-DQA1 in cis of HLA-DQB1*03:01 (DQA1*03:03; DQA1*05:05; DQA1*06:01). This effect may be due to a peptide being presented by all DQ0301 heterodimers (which are tolerant at the P1 binding position), or it may stem from genetic effects of HLA on T cell receptor genes TCRA and TCRB usage that influence the TCR repertoire. Using bulk and single-cell RNA sequencing data across Chinese and Caucasians, who have distinct patterns of linkage disequilibrium around DQB1*03:01, we found that HLA-DQB1*03:01 alters TCR repertoire at specific positions, most significantly within the CDR2α, CDR2β, and CDR3β loops. These results illustrate the remarkable conservation of genetic effects in narcolepsy across ethnicity. The identification of the disease-causing T cells will be crucial for elucidating how this finding relates to the underlying pathophysiology.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (30)
Lisan Zhang
Department of Neurology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University
Shuo Cai
Centre of Biomedical Systems and Informatics, Zhejiang University—University of Edinburgh Institute, Zhejiang University School of Medicine
Ashton Teng
Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University
Ling Lin
Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University
Fang Han
Division of Sleep Medicine, The Peking University People’s Hospital
Han Yan
Seung-Chul Hong
Department of Neuropsychiatry, College of Medicine, St. Vincent’s Hospital, Catholic University of Korea
Fabio Pizza
Department of Biomedical and Neuromotor Sciences, University of Bologna
Giuseppe Plazzi
Istituto di Ricovero e Cura a Carattere Scientifico - IRCCS Institute of Neurological Sciences
Luca Morandi
Department of Biomedical and Neuromotor Sciences, University of Bologna
Ambra Stefani
Department of Neurology, Innsbruck Medical University
Birgit Högl
Department of Neurology, Innsbruck Medical University
Michel Lecendreux
Pediatric Sleep Center and National Reference Center for Narcolepsy and Idiopathic Hypersomnia Hospital Robert Debre
Patrice Bourgin
Department of Sleep Medicine, Strasbourg University Hospital, Strasbourg University
Isabelle Arnulf
Sleep Disorder Unit, Pitié-Salpêtrière Hospital, Assistance Publique-Hopitaux de Paris
Stine Knudsen-Heier
Norwegian Centre of Expertise for Neurodevelopment Disorders and Hypersomnias, Department of Rare Disorders, Oslo University Hospital and University of Oslo
Takashi Kanbayashi
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
Yu-Shu Huang
Poul Jennum
Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital
Karel Sonka
Department of Neurology and Centre of Clinical Neurosciences, First Faculty of Medicine, Charles University and General University Hospital
Sona Nevsimalova
Department of Neurology and Centre of Clinical Neurosciences, First Faculty of Medicine, Charles University and General University Hospital
Makoto Honda
Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science
Fernando Morgadinho Coelho
Departamento de Psicobiologia, Universidade Federal de São Paulo
Zerrin Pelin
Faculty of Health Sciences, Hasan Kalyoncu University
Luigi Ferini-Strambi
Sleep Disorders Center, Division of Neuroscience, Ospedale San Raffaele, Università Vita-Salute
Taku Miyagawa
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo
Seik-Soon Khor
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo
Katsushi Tokunaga
Wanlu Liu
Centre of Biomedical Systems and Informatics, Zhejiang University—University of Edinburgh Institute, Zhejiang University School of Medicine
Emmanuel J. Mignot
Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University