Language

English

Publication Date

2-28-2026

Journal

Respiratory Research

DOI

10.1186/s12931-026-03565-x

PMID

41764487

PMCID

PMC12961773

PubMedCentral® Posted Date

2-28-2026

PubMedCentral® Full Text Version

Post-print

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 FEV1, FVC, and FEV1/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 FEV1, FVC, and FEV1/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.

Keywords

Aged, Female, Humans, Male, Middle Aged, Cohort Studies, Forced Expiratory Volume, Genetic Predisposition to Disease, Genome-Wide Association Study, Lung, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Vital Capacity, Racial Groups, Spirometry, Lung volume measurements, Genomics, Pulmonary disease, Chronic obstructive

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.