Abstract
BACKGROUND: Despite evidence for a genetic component, few genetic associations with lung function decline have been identified. We aimed to evaluate genome-wide associations and putative downstream functionality of genetic variants for lung function decline. METHODS: We conducted genome-wide association study (GWAS) analyses of decline in FEV(1), FVC, and FEV(1)/FVC in 52,056 White (N = 44,988), Black (N = 5,788), Hispanic (N = 550), and Chinese American (N = 730) participants across seven general population cohorts. GWAS analyses were stratified by cohort, ancestry, and sex. Results were combined in cross-ancestry and ancestry-specific meta-analyses. Significant variants available in two independent COPD-enriched cohorts were tested for replication. RESULTS: We identified 361 distinct genome-wide significant (p < 5E-08) variants for one or more of the FEV(1), FVC, and FEV(1)/FVC decline phenotypes, which overlapped with previously reported genetic signals for pulmonary traits. Four variants, or 10.3% of variants available for replication testing, were nominally associated (p < 0.05) with at least one decline phenotype in COPD-enriched cohorts. Gene-level analysis of GWAS results implicated 38 genes, many with consistent associations across ancestries or decline phenotypes. Annotation class analysis revealed enrichment of regulatory processes for corticosteroid biosynthesis and metabolism. Drug repurposing analysis identified 43 approved compounds targeting eight implicated genes. CONCLUSIONS: Our GWAS meta-analyses identified numerous genetic loci associated with lung function decline. These findings contribute knowledge to the genetic architecture of lung function decline, provide evidence for a role of corticosteroids in the etiology of lung function decline, and identify drug targets meriting further study for potential repurposing to slow lung function decline and mitigate lung disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-026-03565-x.