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

Area of Science:

• Genomics
• Molecular Biology
• Cancer Research

Background:

• Genome-wide association studies (GWAS) have identified numerous loci associated with lung cancer risk.
• The precise genetic mechanisms and target genes underlying these GWAS loci remain largely unknown.
• Risk variants often regulate gene expression in a context-specific manner, necessitating cell-type resolution.

Approach:

• Generated a single-cell transcriptome and chromatin accessibility map from 117,911 human lung cells.
• Detected cell-type-specific candidate cis-regulatory elements (cCREs) and identified candidate causal variants (CCVs).
• Colocalized CCVs with cCREs and employed a multi-level cCRE-gene linking system to nominate susceptibility genes.

Key Points:

• Prioritized variants for 68% of GWAS loci through cCRE colocalization, implicating epithelial and immune cells in lung cancer susceptibility.
• Identified candidate susceptibility genes for 57% of lung cancer loci, including novel genes missed by bulk approaches.
• Discovered that adjacent genes in different cell types correlate with distinct CCV subsets, such as JAML and MPZL3.

Conclusions:

• This study reveals the specific cell types and regulatory contexts where lung cancer susceptibility genes are functional.
• Provides a high-resolution map of gene regulation in lung cells to interpret GWAS findings.
• Advances the understanding of lung cancer genetic architecture and identifies potential therapeutic targets.