Genome-wide Association Study Combining UK Biobank and GASP Consortium Highlights Novel Loci Associated with Moderate-Severe Asthma

The genetic architecture of asthma to date has been described by the discovery of around 20 loci from genome-wide association studies (GWAS), primarily with cases covering mild-to-moderate asthma. We hypothesised that moderate-to-severe asthma, which is currently difficult to treat, may have a specific genetic architecture, however there have not been large GWAS of moderate-to-severe asthma.Accordingly, we selected 5,135 European ancestry moderate-severe asthma cases (British Thoracic Society criteria 3 or above) and 25,675 controls free from lung disease, allergic rhinitis and atopic dermatitis, from UK Biobank and the Genetics of Asthma Severity & Phenotypes (GASP) cohort (cases only). We tested 33,771,858 SNPs and indels genome-wide (imputation against combined UK10K and 1000 genomes phase 3 panels) for association with moderate-severe asthma.We identified 23 independent signals associated with moderate-to-severe asthma (P < 5×10-8), including novels signals in or near GATA3, RIC1, ZNF652, RPAP3 and MUC5AC, highlighting regions that harbour variants that effect gene expression or genes that play a role in respiratory disease and immune response. Previously described asthma loci where replicated including signals in or near D2HGDH, CD247, HLA-DQB1, HLA-DQA1, TSLP/WDR36, IL1RL1/IL18R1, CLEC16A, GATA3, IL33, SMAD3, SLC22A5/IL13, C11orf30, ZBTB10, IKZF3-ORMDL3 and IKZF4.This largest GWAS of moderate-severe asthma to date and highlights novel loci that may provide new biological insights relevant to treatment of severe asthma.