Single-Cell Mapping of Genetic Risk Across Ten Respiratory Diseases.

Understanding how genetic risk variants contribute to respiratory diseases requires mapping genome-wide association study (GWAS) signals to disease-relevant cell types and states within the human lung. Here, we integrated GWAS summary statistics for ten major respiratory diseases, including asthma, COPD, idiopathic pulmonary fibrosis (IPF), COVID-19, and lung cancer, using a large-scale single-cell transcriptomic dataset of more than 523,000 cells from the Human Lung Cell Atlas. Applying the single-cell Disease Relevance Score (scDRS) framework, we systematically identified shared and disease-specific cellular associations across four major compartments, namely epithelial, immune, endothelial, and stromal. We found that alveolar type II (AT2) cells represent a central susceptibility hub for asthma, COPD, and COVID-19, whereas disease-specific risk enrichment was observed in subpopulations such as CCL3 alveolar macrophages in COVID-19 and adventitial fibroblasts in asthma. Importantly, subclustering revealed substantial heterogeneity within cell types, with distinct transcriptional programs underlying differential disease associations. For example, AT2 subclusters exhibited divergent susceptibility patterns to asthma versus COVID-19, reflecting immune-interacting versus antiviral states. Our results provide a systematic single-cell framework for linking genetic risk to the cellular architecture of the human lung and uncover both shared and disease-specific mechanisms underlying respiratory disease susceptibility.