Integrative pathway genomics of lung function and airflow obstruction

Area of Science:

• Genomics
• Pulmonology
• Bioinformatics

Background:

• Chronic respiratory disorders represent a significant global health burden.
• Genome-wide association studies (GWASs) have identified loci for lung function but explain limited phenotypic variability.
• Integrating pathway analysis with GWASs may uncover a wider range of genes and processes affecting pulmonary traits.

Purpose of the Study:

• To identify genes and biological processes influencing pulmonary function and airflow obstruction by combining pathway-based methods with GWASs.
• To explore the functional overlap and differences between biological modules associated with lung function and airflow obstruction.
• To identify and validate novel candidate genes for obstructive lung disease.

Main Methods:

• Performed two independent GWASs of lung function and applied gene set enrichment analysis.
• Validated findings using a second independent GWAS dataset.
• Conducted pathway enrichment analysis on a meta-analyzed GWAS of airflow obstruction and performed network analysis.

Main Results:

• Identified 131 significantly enriched gene sets associated with lung function, clustering into modules related to development, immunity, cell signaling, and more.
• Found that gene set enrichment was driven by variants with less stringent P-values, not solely by GWAS-significant loci.
• Discovered overlapping and distinct biological modules for lung function and airflow obstruction, with extracellular matrix (ECM) processes enriched in the latter.
• Implicated matrix metalloproteinase 10 (MMP10) as a candidate gene for obstructive lung disease via network analysis of the ECM module.
• Validated MMP10's role in susceptibility to cigarette smoke-induced emphysema using a knockout mouse model.

Conclusions:

• Integrating pathway analysis with population-based genomics enhances the understanding of biological processes underlying pulmonary function.
• Identified MMP10 as a novel candidate gene for obstructive lung disease, with functional validation in a mouse model.
• This integrated approach provides a broader repertoire of genes and processes influencing lung function and disease.