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, 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.
SIGNIFICANCE
Narcolepsy type 1 is remarkable for its strong transethnic association with human leukocyte antigen (HLA)-DQA1*01:02/DQB1*06:02; only a handful of cases without these alleles have been found. Variation at HLA-DQA1 eliminates susceptibility, and the presence in trans of other HLA-DQA1*01 allele reduces susceptibility. We found that HLA-DQB1*03:01, independent of HLA-DQA1, reduces onset age by 3 y across ethnic groups. HLA-DQB1*03:01 does not form a stable heterodimer with HLA-DQA1*01. Effects of other genome-wide association study (GWAS)-associated polymorphisms were absent or nonsignificant.
This result suggests that narcolepsy occurrence and onset age are regulated by different processes. The HLA-DQA1-independent effect of HLA-DQB1*03:01 on onset age may be explained by peptide binding tolerance at the P1 position or effects on the T cell receptor repertoire.
Web | DOI | PDF | Proceedings of the National Academy of Sciences | Paywall
Zhang, Lisan; Cai, Shuo; Teng, Ashton; Lin, Ling; Han, Fang; Yan, Han; Hong, Seung-Chul; Pizza, Fabio; Plazzi, Giuseppe; Morandi, Luca; Stefani, Ambra; Högl, Birgit; Lecendreux, Michel; Bourgin, Patrice; Arnulf, Isabelle; Knudsen-Heier, Stine; Kanbayashi, Takashi; Huang, Yu-Shu; Jennum, Poul; Sonka, Karel; Nevsimalova, Sona; Honda, Makoto; Coelho, Fernando Morgadinho; Pelin, Zerrin; Ferini-Strambi, Luigi; Miyagawa, Taku; Khor, Seik-Soon; Tokunaga, Katsushi; Liu, Wanlu; Mignot, Emmanuel J
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.
SIGNIFICANCE
Narcolepsy type 1 is remarkable for its strong transethnic association with human leukocyte antigen (HLA)-DQA1*01:02/DQB1*06:02; only a handful of cases without these alleles have been found. Variation at HLA-DQA1 eliminates susceptibility, and the presence in trans of other HLA-DQA1*01 allele reduces susceptibility. We found that HLA-DQB1*03:01, independent of HLA-DQA1, reduces onset age by 3 y across ethnic groups. HLA-DQB1*03:01 does not form a stable heterodimer with HLA-DQA1*01. Effects of other genome-wide association study (GWAS)-associated polymorphisms were absent or nonsignificant.
This result suggests that narcolepsy occurrence and onset age are regulated by different processes. The HLA-DQA1-independent effect of HLA-DQB1*03:01 on onset age may be explained by peptide binding tolerance at the P1 position or effects on the T cell receptor repertoire.
Web | DOI | PDF | Proceedings of the National Academy of Sciences | Paywall