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

Qing Li; Chao Li; Linshuoshuo Lyu; Jifeng Wang; Fangcheng Yuan; Eugene Jeong; Qingyuan Song; Chao Yan; You Chen; Jungyoon Choi; Shuai Xu; Yu Wang; Quanhu Sheng; Wanqing Wen; Martha J. Shrubsole; Qiuyin Cai; Xiao‐Ou Shu; Guimin Gao; Bhuminder Singh; Zhijun Yin; Lori A. Coburn; Kristen Keon Ciombor; Cathy Eng; Joshua A. Bauer; Ulrike Peters; Keith T. Wilson; Wei Zheng; Ken S. Lau; Xingyi Guo

doi:10.64898/2026.10.29.26366877

Genetic & Genomic MedicinemedRxivNov 1, 2026

Preprint

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

Qing Li, Chao Li, Linshuoshuo Lyu iD, Jifeng Wang, Fangcheng Yuan iD, Eugene Jeong iD, Qingyuan Song, Chao Yan iD, You Chen iD, Jungyoon Choi, Shuai Xu iD, Yu Wang iD, Quanhu Sheng iD, Wanqing Wen iD, Martha J. Shrubsole iD, Qiuyin Cai iD, Xiao‐Ou Shu iD, Guimin Gao iD, Bhuminder Singh iD, Zhijun Yin iD, Lori A. Coburn iD, Kristen Keon Ciombor iD, Cathy Eng iD, Joshua A. Bauer iD, Ulrike Peters iD, , Xingyi Guo iD

Abstract

Bulk-tissue transcriptome-wide association studies (TWAS) have identified colorectal cancer (CRC) susceptibility genes, but cell-type-specific regulatory mechanisms remain poorly understood. Here, we performed single-cell TWAS integrating matched germline genotypes and single-cell transcriptomes from normal colorectal mucosa (381 donors) and polyps (84 donors), cell-type-specific chromatin accessibility, and GWAS from 132,261 cases and 1,752,398 controls. We identified 546 gene-cell-type associations implicating 347 candidate susceptibility genes across seven normal and nine polyp epithelial populations, including 213 previously unreported genes, with 74% exhibiting cell-type-specific associations. Integrated co-expression and ChIP-seq analyses revealed distinct TF-risk gene networks, highlighting GATA6, MAX and RAD21 in normal mucosa, and TFAP4- and CEBPB-associated networks in premalignant polyp populations. Further multi-omics analyses supported dysregulation of 233 genes (67%), while drug-target analyses identified 63 potentially druggable genes. DepMap and CRISPR-Cas9 analyses implicated 35 genes in CRC cell viability. These findings reveal cell-type-specific susceptibility mechanisms and prioritize candidate therapeutic targets for CRC prevention.

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