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

Natri, H. M.; Del Azodi, C. B.; Peter, L.; Taylor, C. J.; Chugh, S.; Kendle, R.; Chung, M.-i.; Flaherty, D. K.; Matlock, B. K.; Calvi, C. L.; Blackwell, T. S.; Ware, L. B.; Bacchetta, M.; Walia, R.; Shaver, C. M.; Kropski, J. A.; McCarthy, D. J.; Banovich, N. E.

doi:10.1101/2023.03.17.533161

bioRxiv · 10.1101/2023.03.17.533161

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

Natri, H. M.·Del Azodi, C. B.·Peter, L.·Taylor, C. J.·Chugh, S.·Kendle, R.·Chung, M.-i.·Flaherty, D. K.·Matlock, B. K.·Calvi, C. L.·Blackwell, T. S.·Ware, L. B.·Bacchetta, M.·Walia, R.·Shaver, C. M.·Kropski, J. A.·McCarthy, D. J.·Banovich, N. E.

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Abstract

Common genetic variants confer substantial risk for chronic lung diseases, including pulmonary fibrosis (PF). 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 67 PF and 49 unaffected donors. Employing a pseudo-bulk approach, we mapped expression quantitative trait loci (eQTL) across 38 cell types, observing both shared and cell type-specific regulatory effects. Further, we identified disease-interaction eQTL and demonstrated that this class of associations is more likely to be cell-type specific and linked to cellular dysregulation in PF. Finally, we connected PF 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 eQTL as key regulators of lung homeostasis and disease.

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Natri, H. M., Del Azodi, C. B., Peter, L., Taylor, C. J., Chugh, S., Kendle, R., Chung, M.-i., Flaherty, D. K., Matlock, B. K., Calvi, C. L., Blackwell, T. S., Ware, L. B., Bacchetta, M., Walia, R., Shaver, C. M., Kropski, J. A., McCarthy, D. J., Banovich, N. E.. 2023-03-21. Cell type-specific and disease-associated eQTL in the human lung. https://doi.org/10.1101/2023.03.17.533161

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