Multi-ancestry genome-wide association study reveals novel genetic signals for lung function decline.

Area of Science:

• Genomics
• Pulmonary Medicine
• Genetic Epidemiology

Background:

• Accelerated lung function decline is a key factor in chronic respiratory diseases.
• Genetic factors influence lung function decline, but few associations have been identified.
• Understanding the genetic basis is crucial for developing targeted interventions.

Purpose of the Study:

• To conduct genome-wide association studies (GWAS) to identify genetic variants associated with lung function decline.
• To explore the functional implications of identified genetic variants.
• To investigate potential therapeutic targets for slowing lung function decline.

Main Methods:

• Genome-wide association analyses were performed on lung function decline phenotypes (FEV1, FVC, FEV1/FVC) across multiple diverse cohorts.
• Genotypes were imputed using TOPMed and Haplotype Reference Consortium panels.
• Meta-analyses combined results across ancestries, with replication testing in COPD-enriched cohorts.

Main Results:

• 361 distinct genome-wide significant variants were identified for lung function decline.
• Eight variants showed nominal association in replication cohorts.
• Gene-level analyses implicated 38 genes, with eight showing consistent associations.
• Enrichment analysis suggested a role for corticosteroid biosynthesis and metabolism.

Conclusions:

• Multi-ancestry GWAS meta-analyses identified novel genetic loci associated with lung function decline.
• Findings contribute to understanding the genetic architecture of lung function decline.
• Evidence supports a role for endogenous corticosteroids and identifies potential drug repurposing targets.