Single-cell transcriptome-wide association analysis reveals epithelial cell-specific genetic susceptibility to colorectal cancer

Single-cell TWAS in normal colorectal mucosa and polyps links 546 gene–cell-type associations to 347 colorectal cancer susceptibility genes, with 74% showing cell-type-specific effects.

• Why it matters: Bulk TWAS has found susceptibility loci for colorectal cancer, but it cannot explain which cell types and regulatory programs drive risk.
• What they did: Using matched germline genotypes and single-cell transcriptomes from 381 normal and 84 polyp donors, plus cell-type chromatin accessibility and GWAS (132,261 cases; 1,752,398 controls), the study tested gene–cell-type associations.
• The result: Multi-omics integration supported dysregulation of 233 genes (67%), drug-target analysis flagged 63 potentially druggable genes, and DepMap/CRISPR Cas9 implicated 35 genes for CRC cell viability.

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