A genome-wide association study of asthma-COPD overlap syndrome (ACOS)

Abstract

Individuals with characteristics of both asthma and COPD (asthma-COPD overlap syndrome, ACOS) experience significantly worse outcomes than those with asthma or COPD alone. Despite hundreds of genetic associations with asthma, COPD and lung function, no genetic variants have specifically been associated with ACOS. We hypothesized that there are genetic determinants of ACOS and sought to identify these in a genome-wide association study.

We defined ACOS based on self-reported doctor-diagnosed asthma and spirometric GOLD2+ airflow limitation. We tested 7693381 genetic variants for association with ACOS in 8068 cases and 40360 healthy controls from UK Biobank (stage 1). We identified signals where P<5x10-6 in this analysis, and where P<0.01 in two sensitivity analyses in UK Biobank using (i) controls with asthma but no COPD and (ii) controls with COPD but no asthma. For these signals, we undertook a meta-analysis of the UK Biobank results and results from fifteen independent cohorts with an additional 4301 cases and 48609 controls (stage 2). All cases and controls were of European ancestry.

Thirty-one genetic variants met criteria for inclusion in stage 2. Of these, eight were associated at genome-wide significance (P<5x10-8) and showed stronger evidence of association in the stage 2 meta-analysis than in UK Biobank alone, including signals near HLA-DQB1, C5orf56, GLB1, FAM105A, PHB, TSLP and IL17RD, and an intergenic signal on chromosome 5 not previously associated with asthma, COPD or lung function.

Whilst our results suggest that many genetic variants associated with ACOS are shared with asthma and/or COPD, we identify a new, distinct signal that may implicate cellular pathways characteristic of ACOS.