Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

Valette, Kim; Li, Zhonglin; Bon-Baret, Valentin; Chignon, Arnaud; Bérubé, Jean‐Christophe; Eslami, Ali; Lamothe, Jennifer; Gaudreault, Nathalie; Joubert, Philippe; Obeidat, Ma’en; Berge, Maarten van den; Timens, Wim; Sin, Don D.; Nickle, David C.; Hao, Ke; Labbé, Catherine; Godbout, Krystelle; Côté, Andréanne; Laviolette, Michel; Boulet, Louis‐Philippe; Mathieu, Patrick; Thériault, Sébastien; Bossé, Yohan

doi:10.1038/s42003-021-02227-6

Cited by 107 publications

(66 citation statements)

References 61 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another possibility for our unique nasal findings regards differences in statistical power between the nasal and lung analyses, since the GTEx v7 lung sample size was 383 vs. the 681 nasal samples we analyzed. To evaluate this, we compared our nasal TWAS results to a recently published lung/UK Biobank-asthma TWAS 41 , 42 , which used a larger set of 1038 lung donors and >400,000 subject GWAS. This analysis only identified 55 asthma TWAS genes, with only 1 of the 11 AOA and 3 of 51 COA nasal-specific TWAS genes we identified among them.…”

Section: Discussionmentioning

confidence: 99%

Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

et al. 2022

View full text Add to dashboard Cite

To identify genetic determinants of airway dysfunction, we performed a transcriptome-wide association study for asthma by combining RNA-seq data from the nasal airway epithelium of 681 children, with UK Biobank genetic association data. Our airway analysis identified 95 asthma genes, 58 of which were not identified by transcriptome-wide association analyses using other asthma-relevant tissues. Among these genes were MUC5AC, an airway mucin, and FOXA3, a transcriptional driver of mucus metaplasia. Muco-ciliary epithelial cultures from genotyped donors revealed that the MUC5AC risk variant increases MUC5AC protein secretion and mucus secretory cell frequency. Airway transcriptome-wide association analyses for mucus production and chronic cough also identified MUC5AC. These cis-expression variants were associated with trans effects on expression; the MUC5AC variant was associated with upregulation of non-inflammatory mucus secretory network genes, while the FOXA3 variant was associated with upregulation of type-2 inflammation-induced mucus-metaplasia pathway genes. Our results reveal genetic mechanisms of airway mucus pathobiology.

show abstract

Section: Discussionmentioning

confidence: 99%

Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Of the remaining replicated CNVs, two affect genes also residing in the HLA: a partial deletion of the large, central exon of MUC22 , and a small deletion within the 3’UTR of TAP2 . Genetic variants in the MUC22 gene region [ 21 , 22 ] and in TAP2 [ 2 ] have been previously associated with asthma and asthma-related traits. The final two asthma-associated CNVs are partial gene duplications on chromosome 2 (affecting exons 4–8 of the PRKRA gene and the 3’ end of the CHROMR long non-coding RNA gene) and chromosome 12 (affecting exon 2 of the FBRSL1 gene).…”

Section: Resultsmentioning

confidence: 99%

“…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%

“…The proportion of population variance in asthma risk attributable to genetic variation has been estimated to be between 35 and 95% [ 1 ], and about 200 genetic loci have been associated with asthma [ 2 ]. However, the variants discovered to date only account for a small proportion of heritability [ 2 ], and unmeasured genomic structural variants such as copy number variants (CNVs) may also contribute to genetic risk. Indeed, CNVs have been shown to play a role in a number of common, complex diseases and traits [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

“…Zinc finger E-box binding homeobox 1 (ZEB1), an epithelial-mesenchymal transition (EMT) key regulator, has been reported involved in the airway smooth muscle cell proliferation 39 and nickel exposure-induced impairment of human lung epithelial cells 40 . Through transcriptome-wide association studies, transcription factor RERE was identified as a candidate causal gene of asthma 41 . The whole-genome expression analysis of peripheral blood mononuclear cells indicated that FOSL1 was positively associated with aspirin-intolerant asthma 42 .…”

Section: Discussionmentioning

confidence: 99%

Identification of key genes and pathways between mild-moderate and severe asthmatics via bioinformatics analysis

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Severe asthma is the main reason for death and disability caused by asthma. However, effective biomarkers for severe asthma have not been identified. Here, we aimed to identify potential biomarkers in severe asthma. We identified 202 differentially expressed genes (DEGs) between severe asthma and mild-moderate asthma after integrating the results from GSE69683 and GSE27011 datasets. The enrichment analysis indicated that 202 DEGs were associated with metabolism- and immune-related processes. 10 hub genes were identified by Cytoscape and five of these genes’ AUC (area under the curve) values were greater than 0.6 in GSE69683. The AUC value reached to 0.701 when combined SEC61A1 and ALDH18A1 expression. The expression of the five hub genes was verified in an external dataset. The network analysis revealed that transcription factor (TF) WT1, ZEB1, RERE, FOSL1, and miR-20a may be involved in the development of asthma. In addition, we found cyclosporine and acetaminophen could interact with these hub genes and may be negatively associated with most of the five hub genes according to previous reports. Overall, key genes were identified between mild-moderate and severe asthmatics, which contributed to the understanding of the development of asthma.

show abstract

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

Cited by 107 publications

References 61 publications

Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

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

Identification of key genes and pathways between mild-moderate and severe asthmatics via bioinformatics analysis

Contact Info

Product

Resources

About