PreprintCC BY-NC-NDmedRxiv29 Oct 2026

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

Q. Li
C. Li
L. Lyu
J. Wang
F. Yuan
E. Jeong
Q. Song
C. Yan
Y. Chen
J. Choi
S. Xu
Y. Wang

17 more authors

Q. Sheng
W. Wen
M. J. Shrubsole
Q. Cai
X.-O. Shu
G. Gao
B. Singh
Z. Yin
L. A. Coburn
K. K. Ciombor
C. Eng
J. A. Bauer
U. Peters
K. T. Wilson
W. Zheng
K. S. Lau
X. Guo¹

¹Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil

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.

Early-life colonization by enterotoxigenic Bacteroides fragilis remodels gut epithelial stem cell states to drive colorectal cancer susceptibility
S. K. Russell, E. Valguarnera, J. J. Pak +1
bioRxiv28 Sep 2026PreprintCC BYFull textOncologybioRxiv
Stool host transcriptome reveals gut epithelial cell states and immune dynamics for gastrointestinal diagnosis and monitoring
W. Pan, X. Li, Z. Yang +8
medRxiv31 Oct 2026PreprintLicence not statedFull textGeneral medicinemedRxiv
Single-cell transcriptome profiling of post-treatment and treatment-naïve colorectal cancer: Insights into putative mechanisms of chemoresistance
Grigory Puzanov, Clémence Astier, Dimitris Papakonstantinou +9
Cancer Letters24 Sep 2026Peer-reviewedCC BY 4.0Full text5 citedProteomics & metabolomics General biologyHAL
Fibrinogen Alpha Chain (FGA) Associates With Epithelial-Mesenchymal Transition, Stemness, and the USP-Catenin Complex in Colorectal Cancer.
Hao Lin, Weixu Chen, Qing Li
Stem cells international19 Oct 2026Peer-reviewedCC BYFull textOncologyEurope PMC
MAGI3 Acts as an Intestinal Epithelial Gatekeeper in Inflammation‐Associated Colorectal Cancer by Suppressing the STAT3‐CCL2 Axis and TAM‐Mediated Immunosuppression
Yumeng Yang, Zhigang Bai, Haibo Wang +10
Advanced Science31 Oct 2026Peer-reviewedCC BY 4.0Full textOncologyPMC

Cite

BibTeX RIS

BibTeX

@misc{li2026singlecell,
  title = {{Single-cell transcriptome-wide association analysis reveals epithelial cell-specific genetic susceptibility to colorectal cancer}},
  author = {Q. Li and C. Li and L. Lyu and J. Wang and F. Yuan and E. Jeong and Q. Song and C. Yan and Y. Chen and J. Choi and S. Xu and Y. Wang and Q. Sheng and W. Wen and M. J. Shrubsole and Q. Cai and X.-O. Shu and G. Gao and B. Singh and Z. Yin and L. A. Coburn and K. K. Ciombor and C. Eng and J. A. Bauer and U. Peters and K. T. Wilson and W. Zheng and K. S. Lau and X. Guo},
  howpublished = {medRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.29.26366877},
  url = {https://www.medrxiv.org/content/10.64898/2026.10.29.26366877v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Single-cell transcriptome-wide association analysis reveals epithelial cell-specific genetic susceptibility to colorectal cancer
AU  - Q. Li
AU  - C. Li
AU  - L. Lyu
AU  - J. Wang
AU  - F. Yuan
AU  - E. Jeong
AU  - Q. Song
AU  - C. Yan
AU  - Y. Chen
AU  - J. Choi
AU  - S. Xu
AU  - Y. Wang
AU  - Q. Sheng
AU  - W. Wen
AU  - M. J. Shrubsole
AU  - Q. Cai
AU  - X.-O. Shu
AU  - G. Gao
AU  - B. Singh
AU  - Z. Yin
AU  - L. A. Coburn
AU  - K. K. Ciombor
AU  - C. Eng
AU  - J. A. Bauer
AU  - U. Peters
AU  - K. T. Wilson
AU  - W. Zheng
AU  - K. S. Lau
AU  - X. Guo
PY  - 2026
DA  - 2026/10/29
PB  - medRxiv
DO  - 10.64898/2026.10.29.26366877
UR  - https://www.medrxiv.org/content/10.64898/2026.10.29.26366877v1
AB  - 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.
ER  -

Abstract

Related

Cite