Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Accessible chromatin peak detection identified cell-type-specific candidate cis-regulatory elements (cCREs) from each lung cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs prioritized the variants for 68% of the GWAS loci, a subset of which was also supported by transcription factor abundance and footprinting. cCRE colocalization and single-cell based trait relevance score nominated epithelial and immune cells as the main cell groups contributing to lung cancer susceptibility. Notably, cCREs of rare proliferating epithelial cell types, such as AT2-proliferating (0.13%) and basal cells (1.8%), overlapped with CCVs, including those in TERT. A multi-level cCRE-gene linking system identified candidate susceptibility genes from 57% of lung cancer loci, including those not detected in tissue- or cell-line-based approaches. cCRE-gene linkage uncovered that adjacent genes expressed in different cell types are correlated with distinct subsets of coinherited CCVs, including JAML and MPZL3 at the 11q23.3 locus. Our data revealed the cell types and contexts where the lung cancer susceptibility genes are functional.

Context-aware single-cell multiome approach identified cell-type specific lung cancer susceptibility genes