Single-cell transcriptome-wide association analysis reveals epithelial cell-specific genetic susceptibility to colorectal cancer
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.
Authors
- Cathy Eng (ORCID: https://orcid.org/0000-0003-2335-0612)
- Fangcheng Yuan (ORCID: https://orcid.org/0000-0002-8443-6754)
- Qiuyin Cai (ORCID: https://orcid.org/0000-0002-9384-5648)
- Guimin Gao (ORCID: https://orcid.org/0000-0001-5556-7141)
- Keith T. Wilson (ORCID: https://orcid.org/0000-0003-4421-1830)
- Kristen Keon Ciombor (ORCID: https://orcid.org/0000-0002-8992-9515)
- Eugene Jeong (ORCID: https://orcid.org/0000-0001-8240-1198)
- Ulrike Peters (ORCID: https://orcid.org/0000-0001-5666-9318)
- Martha J. Shrubsole (ORCID: https://orcid.org/0000-0002-5591-7575)
- Ken S. Lau (ORCID: https://orcid.org/0000-0001-8438-0319)
- Joshua A. Bauer (ORCID: https://orcid.org/0000-0002-8019-900X)
- Lori A. Coburn (ORCID: https://orcid.org/0000-0003-3249-9806)
- Xiao‐Ou Shu (ORCID: https://orcid.org/0000-0002-0711-8314)
- Wanqing Wen (ORCID: https://orcid.org/0000-0002-3004-5168)
- Bhuminder Singh (ORCID: https://orcid.org/0000-0003-1357-2158)
- You Chen (ORCID: https://orcid.org/0000-0001-8232-8840)
- Chao Yan
- Quanhu Sheng (ORCID: https://orcid.org/0000-0001-8951-9295)
- Linshuoshuo Lyu (ORCID: https://orcid.org/0000-0003-2862-7772)
- Yu Wang (ORCID: https://orcid.org/0000-0003-3850-5162)
- Qingyuan Song
- Zhijun Yin
- Qing Li
- Wei Zheng
- Jifeng Wang
- Xingyi Guo
- Jungyoon Choi
- Shuai Xu
- Chao Li
Institutions
- Vanderbilt University (US)
- University of Washington (US)
- University of Chicago (US)
- Fred Hutch Cancer Center (US)
- VA Tennessee Valley Healthcare System (US)
- Nashville VA Medical Center (US)
- Vanderbilt-Ingram Cancer Center (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- medRxiv
- Published
- 2026-11-01
- DOI
- https://doi.org/10.64898/2026.10.29.26366877
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- preprint
Funders
- U.S. Department of Veterans Affairs
- Leona M. and Harry B. Helmsley Charitable Trust
- UCLA Health System
- Vanderbilt University Medical Center
- National Institutes of Health
- David Geffen School of Medicine, University of California, Los Angeles
- Clinical and Translational Science Institute, University of California, Los Angeles