Eleven loci with new reproducible genetic associations with allergic disease risk

the 23 and Me Research Team, the collaborators of the SHARE study

Research output: Contribution to journalArticle (Academic Journal)

16 Citations (Scopus)
234 Downloads (Pure)

Abstract

Background: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities. Objective: We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects. Methods: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study. Results: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10−6. Of these, 20 were also significantly associated (P <.05/30 =.0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses. Conclusion: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.

Original languageEnglish
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Early online date19 Apr 2018
DOIs
Publication statusE-pub ahead of print - 19 Apr 2018

Keywords

  • atopic dermatitis
  • atopy
  • genome-wide association study
  • Rhinitis
  • transcriptome

Fingerprint Dive into the research topics of 'Eleven loci with new reproducible genetic associations with allergic disease risk'. Together they form a unique fingerprint.

  • Projects

    MRC UoB UNITE Unit - Programme 1

    Davey Smith, G.

    1/06/1331/03/18

    Project: Research

    Cite this