The Genomic Revolution in Pulmonary Medicine: A Comprehensive Narrative Review of Genomic and Multi-Omic Technologies in Respiratory Conditions

Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung diseases (ILDs), represent a major global health burden. Their significant clinical and biological heterogeneity complicates diagnosis and limits the efficacy of traditional, one-size-fits-all management approaches. The advent of high-throughput genomic and multi-omic technologies has initiated a paradigm shift from syndromic classification to molecular-based endotyping. A narrative review of the literature was performed, synthesising foundational and recent research in the genomics, epigenomics, and multi-omics of chronic respiratory diseases. Key studies were selected based on their relevance to genetic architecture, biomarker development, and translational applications in precision medicine. We discuss the complex genetic architecture of pulmonary conditions, highlighting the contribution of both rare, high-penetrance variants, such as SERPINA1, CFTR, and BMPR2, and polygenic risk from many common variants, such as HHIP, FAM13A, and IL33. We provide detailed analyses of polygenic risk scores (PRSs) for COPD and asthma, including their construction, validation across ancestries, and predictive performance. We detail how integrative multi-omic approaches, including transcriptomics, proteomics, and metabolomics, are successfully defining molecular endotypes, such as Type 2-high asthma, which, in turn, inform the use of targeted biologic therapies. Finally, we review the development of molecular diagnostics, including metagenomic sequencing of infections and liquid biopsies for lung cancer and the development of prognostic biomarkers. The genomic revolution is transforming pulmonary medicine through the discovery of novel disease pathways, precise molecular classification, and the recognition of new therapeutic targets. Despite major challenges in functional interpretation, data integration, and clinical–translational equity, these technologies hold the key to a new era of personalised respiratory health and precision medicine.