Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes.

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate 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. Identified candidate cis-regulatory elements (cCREs) are largely cell type-specific, with 37% detected in one cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs combined with transcription factor footprinting prioritize the variants for 68% of the GWAS loci. CCV-colocalization and trait relevance score indicate that epithelial and immune cell categories, including rare cell types, contribute to lung cancer susceptibility the most. A multi-level cCRE-gene linking system identifies candidate susceptibility genes from 57% of the loci, where most loci display cell-category-specific target genes, suggesting context-specific susceptibility gene function.