학술논문
Cell-type-specific and disease-associated expression quantitative trait loci in the human lung
Document Type
Article
Author
Natri, Heini M.; Del Azodi, Christina B.; Peter, Lance; Taylor, Chase J.; Chugh, Sagrika; Kendle, Robert; Chung, Mei-i; Flaherty, David K.; Matlock, Brittany K.; Calvi, Carla L.; Blackwell, Timothy S.; Ware, Lorraine B.; Bacchetta, Matthew; Walia, Rajat; Shaver, Ciara M.; Kropski, Jonathan A.; McCarthy, Davis J.; Banovich, Nicholas E.
Source
Nature Genetics; April 2024, Vol. 56 Issue: 4 p595-604, 10p
Subject
Language
ISSN
10614036; 15461718
Abstract
Common genetic variants confer substantial risk for chronic lung diseases, including pulmonary fibrosis. Defining the genetic control of gene expression in a cell-type-specific and context-dependent manner is critical for understanding the mechanisms through which genetic variation influences complex traits and disease pathobiology. To this end, we performed single-cell RNA sequencing of lung tissue from 66 individuals with pulmonary fibrosis and 48 unaffected donors. Using a pseudobulk approach, we mapped expression quantitative trait loci (eQTLs) across 38 cell types, observing both shared and cell-type-specific regulatory effects. Furthermore, we identified disease interaction eQTLs and demonstrated that this class of associations is more likely to be cell-type-specific and linked to cellular dysregulation in pulmonary fibrosis. Finally, we connected lung disease risk variants to their regulatory targets in disease-relevant cell types. These results indicate that cellular context determines the impact of genetic variation on gene expression and implicates context-specific eQTLs as key regulators of lung homeostasis and disease.