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

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, <i>P</i> = 1.7 × 10<sup>-18</sup>) showed no heterogeneity across ethnic groups and was independent of common allelic variation at HLA-DQA1 in <i>cis</i> 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.

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Journal
Proceedings of the National Academy of Sciences
Published
2025-12-09
DOI
https://doi.org/10.1073/pnas.2513989122
Primary Topic
Sleep and Wakefulness Research
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article
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article

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

Lisan Zhang, Shuo Cai, Karel Šonka, Fabio Pizza et al.
Proceedings of the National Academy of Sciences
Sleep and Wakefulness Research
article

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

Lisan Zhang, Shuo Cai, Karel Šonka, Fabio Pizza, Soňa Nevšímalová, Seung‐Chul Hong, Taku Miyagawa, Stine Knudsen, Luca Morandi, Katsushi Tokunaga, Birgit Högl, Michel Lecendreux, Poul Jennum, Seik‐Soon Khor, Patrice Bourgin, Isabelle Arnulf, Ashton Teng, Emmanuel Mignot, Luigi Ferini‐Strambi, Yu‐Shu Huang, Fernando Morgadinho Santos Coelho, Zerrin Pelin, Fang Han, Wanlu Liu, Makoto Honda, Takashi Kanbayashi, Han Yan, Ling Lin, Ambra Stefani, Giuseppe Plazzi
article en

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, <i>P</i> = 1.7 × 10<sup>-18</sup>) showed no heterogeneity across ethnic groups and was independent of common allelic variation at HLA-DQA1 in <i>cis</i> 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.

Proceedings of the National Academy of SciencesVol. 122(50)
Oslo University Hospital (NO), Memorial Hospital of South Bend (US), Innsbruck Medical University (AT), University of Tsukuba (JP), Vita-Salute San Raffaele University (IT), Chang Gung University (TW), Peking University (CN), Charles University (CZ), Glostrup Hospital (DK), Sir Run Run Shaw Hospital (CN), Chang Gung Memorial Hospital (TW), Sorbonne Université (FR), The Catholic University of Korea St. Vincent's Hospital (KR), Seiwa Hospital (JP), Taoyuan Chang Gung Memorial Hospital (TW), Assistance Publique – Hôpitaux de Paris (FR), Tokyo Metropolitan Institute of Medical Science (JP), Pitié-Salpêtrière Hospital (FR), Peking University People's Hospital (CN), Hôpital Robert-Debré (FR), IRCCS Ospedale San Raffaele (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Hasan Kalyoncu University (TR), Zhejiang University-University of Edinburgh Institute (CN), General University Hospital in Prague (CZ), Université de Strasbourg (FR), The University of Tokyo (JP), Zhejiang University (CN), Universidade Federal de São Paulo (BR), University of Bologna (IT), Stanford University (US), Tsukuba International University (JP)
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