Planer, J. D.; Morley, M. P. D.; Cai, S.; Peterson, A. R.; Lu, M.; Yang, Y.; Hallquist, H.; Schaefer, S. E.; Carl, J.; Zhou, S.; Lin, S. M.; Chandrasekaran, P.; Young, L. R.; Cantu, E.; Peranteau, W.; Frank, D. B.; Morrisey, E.; Basil, M. C.

At birth, the lungs undergo an abrupt physiologic change, as the function of gas exchange transitions from the placenta to the lung. Subsequent postnatal development of the lungs is marked by a rapid and profound increase in the growth of the distal airways and alveolar gas exchange compartment. Insults during this period increase the risk of developing lung disease later in life, though how early-life events affect adult disease onset remains unclear. We generated a single-cell atlas of postnatal human lung development from birth through adulthood and mapped temporally regulated gene expression changes in each cell lineage. Using this atlas, we identified disease risk-associated genes with developmentally regulated expression. These analyses reveal cell type-specific and temporally restricted expression of genes associated with adult lung disease risk, including COPD. Heritability enrichment analysis demonstrated that COPD genetic risk is enriched in genes active during early postnatal endothelial development, linking early-life vascular maturation to adult disease susceptibility. These findings characterize the early window of susceptibility for adult chronic lung diseases and establish a framework to guide mechanistic studies of disease-associated genes.