A genome-wide association study of asthma hospitalizations in adults

Yan, Qi; Forno, Erick; Herrera‐Luis, Esther; Pino-Yanes, María; Yang, Ge; Oh, Sam S.; Acosta‐Pérez, Edna; Hu, Donglei; Eng, Celeste; Huntsman, Scott; Rodríguez‐Santana, José; Cloutier, Michelle M.; Canino, Glorisa; Burchard, Esteban G.; Chen, Wei; Celedón, Juan C.

doi:10.1016/j.jaci.2020.08.020

Cited by 24 publications

(16 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the HLA-DQ locus was the first genetic locus to be associated with asthma (26). Since then, many genetic studies have identified associations between HLA genes and susceptibility to asthma (2,18,20,27), as well as asthma subtypes (17,19,28,29) and related traits such as serum IgE levels (30,31). Our finemapping analysis suggest that there are at least two independent genetic risk loci for asthma within the HLA region.…”

Section: Discussionmentioning

confidence: 99%

Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank

Fawcett

Demidov

Shrine

et al. 2021

Preprint

View full text Add to dashboard Cite

BackgroundThe role of copy number variants (CNVs) in susceptibility to asthma is not well understood. This is, in part, due to the difficulty of accurately measuring CNVs in large enough sample sizes to detect associations. The recent availability of whole-exome sequencing (WES) in large biobank studies provides an unprecedented opportunity to study the role of CNVs in asthma.MethodsWe called common CNVs in 49,953 individuals in the first release of UK Biobank WES using ClinCNV software. CNVs were tested for association with asthma in a stage 1 analysis comprising 7,098 asthma cases and 36,578 controls from the first release of sequencing data. Nominally-associated CNVs were then meta-analysed in stage 2 with an additional 17,280 asthma cases and 115,562 controls from the second release of UK Biobank exome sequencing, followed by validation and fine-mapping.ResultsFive of 189 CNVs were associated with asthma in stage 2, including a deletion overlapping the HLA-DQA1 and HLA-DQB1 genes, a duplication of CHROMR/PRKRA, deletions within MUC22 and TAP2, and a duplication in FBRSL1. The HLA-DQA1, HLA-DQB1, MUC22 and TAP2 genes all reside within the human leukocyte antigen (HLA) region on chromosome 6. In silico analyses demonstrated that the deletion overlapping HLA-DQA1 and HLA-DQB1 is likely to be an artefact arising from under-mapping of reads from non-reference HLA haplotypes, and that the CHROMR/PRKRA and FBRSL1 duplications represent presence/absence of pseudogenes within the HLA region. Bayesian fine-mapping of the HLA region suggested that there are two independent asthma association signals. The variants with the largest posterior inclusion probability in the two credible sets were an amino acid change in HLA-DQB1 (glutamine to histidine at residue 253) and a multi-allelic amino acid change in HLA-DRB1 (presence/absence of serine, glycine or leucine at residue 11).ConclusionsAt least two independent loci characterised by amino acid changes in the HLA-DQA1, HLA-DQB1 and HLA-DRB1 genes are likely to account for association of SNPs and CNVs in this region with asthma. The high divergence of haplotypes in the HLA can give rise to spurious CNVs, providing an important, cautionary tale for future large-scale analyses of sequencing data.

show abstract

Section: Discussionmentioning

confidence: 99%

Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank

Fawcett

Demidov

Shrine

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Further studies should consider grouping HLA alleles according to their primary biological function rather than by the name of the allele 39 . Finally, in a recent study, a significant association was shown between the HLA‐DQB1 loci and asthma severity 40 . Interestingly, 5 of the 19 significant associations observed in our study regard HLA‐DQB1 alleles.…”

Section: Discussionmentioning

confidence: 44%

Associations between specific IgE sensitization to 26 respiratory allergen molecules and HLA class II alleles in the EGEA cohort

Gheerbrant

Guillien

Vernet

et al. 2021

Allergy

View full text Add to dashboard Cite

Background: Allergy, the most frequent immune disorder affecting 30% of the world's population, is the consequence of immunoglobin E (IgE) sensitization to allergens. Among the genetic factors suspected to be involved in allergy, the HLA class-II genomic region is a strong candidate.Objective: To assess the association between HLA class-II alleles and specific IgE (sIgE) sensitization to a large number of respiratory allergen molecules. Methods:The analysis relied on 927 participants of the EGEA cohort, including 497 asthmatics. The study focuses on 26 aeroallergens recognized by sIgE in at least 5% of the study population (determined with the MEDALL chip with sIgE ≥ 0.3 ISU) and 23 imputed HLA class-II alleles. For each sIgE sensitization and HLA class-II allele, we fitted a logistic regression model accounting for familial dependence and adjusted for

show abstract

“…Indeed, the HLA-DQ locus was the first genetic locus to be associated with asthma [ 26 ]. Since then, many genetic studies have identified multiple, independent associations between HLA genes and susceptibility to asthma [ 2 , 18 , 20 , 27 – 29 ], as well as asthma subtypes [ 17 , 19 , 30 , 31 ] and related traits such as serum IgE levels [ 32 , 33 ]. Our fine-mapping analysis suggest that there are at least two independent genetic risk loci for asthma within the HLA region.…”

Section: Discussionmentioning

confidence: 99%

Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank

et al. 2022

View full text Add to dashboard Cite

Background The role of copy number variants (CNVs) in susceptibility to asthma is not well understood. This is, in part, due to the difficulty of accurately measuring CNVs in large enough sample sizes to detect associations. The recent availability of whole-exome sequencing (WES) in large biobank studies provides an unprecedented opportunity to study the role of CNVs in asthma. Methods We called common CNVs in 49,953 individuals in the first release of UK Biobank WES using ClinCNV software. CNVs were tested for association with asthma in a stage 1 analysis comprising 7098 asthma cases and 36,578 controls from the first release of sequencing data. Nominally-associated CNVs were then meta-analysed in stage 2 with an additional 17,280 asthma cases and 115,562 controls from the second release of UK Biobank exome sequencing, followed by validation and fine-mapping. Results Five of 189 CNVs were associated with asthma in stage 2, including a deletion overlapping the HLA-DQA1 and HLA-DQB1 genes, a duplication of CHROMR/PRKRA, deletions within MUC22 and TAP2, and a duplication in FBRSL1. The HLA-DQA1, HLA-DQB1, MUC22 and TAP2 genes all reside within the human leukocyte antigen (HLA) region on chromosome 6. In silico analyses demonstrated that the deletion overlapping HLA-DQA1 and HLA-DQB1 is likely to be an artefact arising from under-mapping of reads from non-reference HLA haplotypes, and that the CHROMR/PRKRA and FBRSL1 duplications represent presence/absence of pseudogenes within the HLA region. Bayesian fine-mapping of the HLA region suggested that there are two independent asthma association signals. The variants with the largest posterior inclusion probability in the two credible sets were an amino acid change in HLA-DQB1 (glutamine to histidine at residue 253) and a multi-allelic amino acid change in HLA-DRB1 (presence/absence of serine, glycine or leucine at residue 11). Conclusions At least two independent loci characterised by amino acid changes in the HLA-DQA1, HLA-DQB1 and HLA-DRB1 genes are likely to account for association of SNPs and CNVs in this region with asthma. The high divergence of haplotypes in the HLA can give rise to spurious CNVs, providing an important, cautionary tale for future large-scale analyses of sequencing data.

show abstract

A genome-wide association study of asthma hospitalizations in adults

Cited by 24 publications

References 41 publications

Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank

Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank

Associations between specific IgE sensitization to 26 respiratory allergen molecules and HLA class II alleles in the EGEA cohort

Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank

Contact Info

Product

Resources

About