This study was conducted to investigate the genetic control of gene expression in a cell-type and context-specific manner in the human lung. We performed single-cell RNA-sequencing (scRNA-seq) of lung tissue from 66 Interstitial Lung Disease (ILD) cases and 48 unaffected donors. Employing a pseudo-bulk approach, we mapped expression quantitative trait loci (eQTL) across 38 cell types. The scRNA-seq data presented here include previously published (<a href="https://pubmed.ncbi.nlm.nih.gov/34262047/">PMID 34262047</a>) and unpublished samples. ILD tissue samples were obtained from lungs removed at the time of lung transplantation at either <a href="https://www.vumc.org/main/home">Vanderbilt University Medical Center</a> (VUMC) or the <a href="https://www.supportstjosephs.org/nortonthoracicinstitute">Norton Thoracic Institute</a> (NTI). Control tissue samples were obtained from lungs declined for organ donation either at the <a href="https://www.dnaz.org/">Donor Network of Arizona</a> (DNA) or VUMC. The self-reported ethnicities of donors were 66.7% European, 9.6% African American, 17.5% not available (N/A), and 6.1% other. The smoking history includes 46.5% ever smoker, 29.8% never smoker, 23.7% N/A. For genotyping, flash-frozen tissue in DNA/RNA shield was homogenized via a bullet blender. Genomic DNA was extracted using Zymo Quick DNA/RNA microprep plus kit. Library preparation and low-pass Whole Genome Sequencing (WGS) were carried out at TGen or by Gencove Inc. At TGen, libraries were prepared using PCR-free Watchmaker kits (Watchmaker Genomics) with 200 ng input. Genomes were sequenced on NovaSeq at low coverage (typically 0.4–1x). The resulting sequence data were processed and imputed using Gencove's imputation platform.

Cell Type-Specific and Disease-Associated eQTL in the Human Lung

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