Rationale Accelerated decline in lung function contributes to the development of chronic respiratory disease. Despite evidence for a genetic component, few genetic associations with lung function decline have been identified. Objectives To evaluate genome-wide associations and putative downstream functionality of genetic variants with lung function decline in diverse general population cohorts. Methods We conducted genome-wide association study (GWAS) analyses of decline in the forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and their ratio (FEV1/FVC) in participants across six cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. Genotypes were imputed to TOPMed (CHARGE cohorts) or Haplotype Reference Consortium (HRC) (UK Biobank) reference panels, and GWAS analyses used generalized estimating equation models with robust standard error. Models were stratified by cohort, ancestry, and sex, and adjusted for important lung function confounders and genotype principal components. Results were combined in cross-ancestry and ancestry-specific meta-analyses. Selected top variants were tested for replication in two independent COPD-enriched cohorts. Measurements and Main Results Our discovery analyses included 52,056 self-reported White (N=44,988), Black (N=5,788), Hispanic (N=550), and Chinese American (N=730) participants with a mean of 2.3 spirometry measurements and 8.6 years of follow-up. Functional mapping of GWAS meta-analysis results identified 361 distinct genome-wide significant (p<5E-08) variants in one or more of the FEV1, FVC, and FEV1/FVC decline phenotypes, which overlapped with previously reported genetic signals for several related pulmonary traits. Of these, 8 variants, or 20.5% of the variant set available for replication testing, were nominally associated (p<0.05) with at least one decline phenotype in COPD-enriched cohorts (White [N=4,778] and Black [N=1,118]). Using the GWAS results, gene-level analysis implicated 38 genes, including eight (XIRP2, GRIN2D, SATB1, MARCHF4, SIPA1L2, ANO5, H2BC10, and FAF2) with consistent associations across ancestries or decline phenotypes. Annotation class analysis revealed significant enrichment of several regulatory processes for corticosteroid biosynthesis and metabolism. Drug repurposing analysis identified 43 approved compounds targeting eight of the implicated 38 genes. Conclusions Our multi-ancestry 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 endogenous corticosteroids in the etiology of lung function decline, and identify drug targets that merit further study for potential repurposing to slow lung function decline and treat lung disease.

BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. No other authors have declared competing interests.

This work was supported by NIH National Heart, Lung, and Blood Institute (NHLBI) award R01HL149352 and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) award T32DK007158. The content is solely the responsibility of the authors and does not represent the official views of the NIH. Funding sources for the individual cohorts contributing to this work are described in the footnotes section.

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Ethics committees/IRBs of Cornell University and RTI international gave ethical approval for this work

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