Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Nick Shrine
  • Michael A. Portelli
  • Catherine John
  • María Soler Artigas
  • Neil Bennett
  • Robert Hall
  • Jon Lewis
  • Amanda P. Henry
  • Charlotte K. Billington
  • Azaz Ahmad
  • Richard J. Packer
  • Dominick Shaw
  • Zara E.K. Pogson
  • Andrew Fogarty
  • Tricia M. McKeever
  • Amisha Singapuri
  • Liam G. Heaney
  • Adel H. Mansur
  • Rekha Chaudhuri
  • Neil C. Thomson
  • John W. Holloway
  • Gabrielle A. Lockett
  • Peter H. Howarth
  • Ratko Djukanovic
  • Kian Fan Chung
  • Peter J. Sterk
  • John D. Blakey
  • Ian M. Adcock
  • Sile Hu
  • Yike Guo
  • Maen Obeidat
  • Don D. Sin
  • Maarten van den Berge
  • David C. Nickle
  • Yohan Bossé
  • Martin D. Tobin
  • Ian P. Hall
  • Christopher E. Brightling
  • Louise V. Wain
  • Ian Sayers

Abstract

Background: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma. Methods: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10−6 in stage 1. We set genome-wide significance at p less than 5 × 10−8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls. Findings: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88–0·93; p=1·76 × 10−10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06–1·12; p=2·32 × 10−8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08–1·16; p=3·06 × 10−9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10−5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022). Interpretation: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population. Funding: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.

Bibliographical metadata

Original languageEnglish
Pages (from-to)20-34
Number of pages15
JournalThe Lancet Respiratory Medicine
Volume7
Issue number1
Early online date11 Dec 2018
DOIs
Publication statusPublished - 1 Jan 2019