Cell type-specific and disease-associated eQTL in the human lung

Understanding how the genetic control of gene expression varies between cell types and contexts is key for our understanding of complex traits including disease. To this end, we leveraged single cell RNA sequencing (scRNA-seq) to characterize the genetic architecture of gene regulation in an organ with one of the most cellularly diverse organs, the human lung. We profile these effects across two conditions, tissue samples from healthy controls and patients with pulmonary fibrosis (PF), a chronic, progressive condition characterized by the scarring of lung tissue. In total, we have generated expression profiles of 475,047 cells from primary human lung tissue from 116 individuals, including 67 with PF and 49 unaffected donors. Employing a pseudo-bulk approach, we have mapped expression quantitative trait loci (eQTL) across 38 cell types, identifying shared and cell type-specific effects. Further, we identify disease-interaction eQTL demonstrating this class of associations are more likely to be cell-type specific and linked to key drivers of dysregulation in PF. Finally, we connect PF risk variants implicated by genome-wide association studies to their regulatory targets in disease-relevant cell types. This study represents the first use of scRNA-seq to identify cell type level eQTL in the human lung, and one of only a small number of studies to carry out these characterizations in solid tissues. These results provide valuable insights into lung biology and disease risk. Overall design: Lung tissue samples were collected from a total of 60 individuals, including 33 ILD cases and 27 nonfibrotic controls, and processed as previously described by Habermann et al (Sci Adv 6, eaba1972, 2020): ILD tissue samples were obtained from lungs removed at the time of lung transplantation at either Vanderbilt University Medical Center (VUMC) or the National Thoracic Institute (NTI). Control tissue samples were obtained from lungs declined for organ donation either at the Donor Network of Arizona (DNA) or VUMC. Tissue sections were taken from multiple peripheral (within ~2 cm of the pleural surface) regions in each lung. For ILD lungs, representatively diseased areas were selected on the basis of preoperative chest CT, while for control lungs, the most normal-appearing region was identified by gross inspection and selected for biopsy. For ILD lungs, diagnoses were determined according to the American Thoracic Society/European Respiratory Society consensus criteria.