Abstract / Summary
Abstract Background Bronchiectasis is an increasingly recognized chronic airway disease with incompletely defined genetic architecture and limited mechanism-informed therapeutic targets. Its overlap with COPD, asthma, and chronic bronchitis suggests shared but unresolved biological mechanisms. Methods We performed ancestry-specific GWAS meta-analyses of bronchiectasis in European and East Asian populations, followed by a joint trans-ancestry meta-analysis including 16,030 cases and 1,841,141 controls. Statistical fine-mapping was then performed. Proteome-wide cis-pQTL-based Mendelian randomization and lung TWAS, together with colocalization analyses, were used to prioritize candidate molecular targets. Genetic correlation, pleiotropy, cis-eQTL-based Mendelian randomization, and colocalization analyses characterized genetic mechanisms shared between bronchiectasis with COPD, asthma, and chronic bronchitis. Results Meta-GWAS identified 5 bronchiectasis lead loci in Europeans, and 1 locus in East Asians. The trans-ancestry analysis identified 5 lead signals, with the strongest association at rs28929474 annotated to SERPINA1 . Fine-mapping identified 2 credible sets in Europeans and 3 in the trans-ancestry analysis. European proteome-wide cis-pQTL analyses with colocalization prioritized AIF1 and WWP2 for bronchiectasis, while East Asian analyses nominated HSPA1A and DXO as candidate proteins. Lung TWAS with colocalization prioritized CHP2 and FUBP1 in Europeans. Cross-disease pleiotropic analyses highlighted shared signals including SERPINA1 , SMAD3 , CFTR , and PHTF1 , with additional blood cis-eQTL support for SMAD3 . Conclusions This study refines the cross-ancestry genetic architecture of bronchiectasis and prioritizes candidate molecular targets within the chronic airway disease spectrum.