BACKGROUND: Some individuals have characteristics of both asthma and chronic obstructive pulmonary disease (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap cases and 40,360 controls without asthma or COPD of European ancestry in UK Biobank (Stage 1). We followed up promising signals which had p<5×10-6, and that remained associated in analyses comparing: i) asthma-COPD overlap vs asthma-only controls, and ii) asthma-COPD overlap versus COPD-only controls). These variants were analysed in 12 independent cohorts (Stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P<5x10-8) for asthma-COPD overlap (meta-analysis of Stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.