Mixed-model and transcriptome-wide association analyses identify transcription factors and genes associated with colorectal cancer susceptibility

Susceptibility transcription factors (TF) whose DNA bindings are altered by genetic variants regulating colorectal cancer (CRC) risk genes remain poorly defined. Using generalized linear mixed models, we analyze 218 TF ChIP-Seq datasets alongside GWAS data from 100,204 CRC cases and 154,587 controls of East Asian and European ancestries. We identify 51 TFs and TF-cofactor interactions, including VDR-cofactors, as key regulators of CRC risk. Integrating these TF insights with transcriptome-wide association studies (TWAS), we further evaluate associations between genetically predicted gene expression, alternative splicing, and alternative polyadenylation with CRC risk, using RNA-seq data from 364 Asian-ancestry and 707 European-ancestry individuals. Multi-ancestry TWAS identify 222 risk genes, including 95 novel genes and 48 potentially druggable targets. Single-cell analysis provides additional functional evidence supporting ~45% of these genes, and experimental validation confirms oncogenic roles for RHPN2, IRS2, and TXN. Our findings elucidate key TF-gene regulatory networks and uncover novel CRC risk genes.

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Journal
Nature Communications
Published
2026-01-15
DOI
https://doi.org/10.1038/s41467-025-68127-z
Primary Topic
Genetic Associations and Epidemiology
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article
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article

Mixed-model and transcriptome-wide association analyses identify transcription factors and genes associated with colorectal cancer susceptibility

Yang-Song, Qiuyin Cai, Christopher H. Dampier, Xinyi Guo et al.
Nature Communications
Genetic Associations and Epidemiology
article

Mixed-model and transcriptome-wide association analyses identify transcription factors and genes associated with colorectal cancer susceptibility

Yang-Song, Qiuyin Cai, Christopher H. Dampier, Xinyi Guo, S. H. Jee, Wu Lan, Xiang Shu, Jie Ping, Zefang Ren, Jae Hwan Oh, Jirong Long, Li Bingshan, Z.W. Chen, Jiajun Shi, Stephen B. Gruber, Ian Tomlinson, Richard Houlston, Wenqiang Song, Luc Van Kaer, Chao Li, Isao Oze, Qing Li, Jifeng Wang, Li Li, Graham Casey, Sun-Seog Kweon, Minta Thomas, Ceres Fernandez-Rozadilla, Maria N. Timofeeva, Ferran Moratalla-Navarro, Malcolm G. Dunlop, Chizu Tanikawa, Philip J. Law, Jing Gao, Vicente Martin, Ulrike Peters, Yoichiro Kamatani, Victor Moreno, Yoon-Ok Ahn, Nan Wang, Keum Ji Jung, Dong-Hyun Kim, Koichi Matsuda, Wanqing Wen, Aesun Shin, Li Hsu, Xiao-Ou Shu, Zhi-Zhong Pan, Gong Yang, Wei Zheng, Yu-Tang Gao, Jeongseon Kim, Jeroen R. Huyghe, Keitaro Matsuo, Wei-Hua Jia, Stephanie L. Schmit
article en

Abstract

Susceptibility transcription factors (TF) whose DNA bindings are altered by genetic variants regulating colorectal cancer (CRC) risk genes remain poorly defined. Using generalized linear mixed models, we analyze 218 TF ChIP-Seq datasets alongside GWAS data from 100,204 CRC cases and 154,587 controls of East Asian and European ancestries. We identify 51 TFs and TF-cofactor interactions, including VDR-cofactors, as key regulators of CRC risk. Integrating these TF insights with transcriptome-wide association studies (TWAS), we further evaluate associations between genetically predicted gene expression, alternative splicing, and alternative polyadenylation with CRC risk, using RNA-seq data from 364 Asian-ancestry and 707 European-ancestry individuals. Multi-ancestry TWAS identify 222 risk genes, including 95 novel genes and 48 potentially druggable targets. Single-cell analysis provides additional functional evidence supporting ~45% of these genes, and experimental validation confirms oncogenic roles for RHPN2, IRS2, and TXN. Our findings elucidate key TF-gene regulatory networks and uncover novel CRC risk genes.

Nature CommunicationsVol. 17(1)
City Of Hope National Medical Center (US), Cleveland Clinic (US), Memorial Sloan Kettering Cancer Center (US), Seoul National University (KR), Institute of Cancer Research (GB), Hallym University (KR), Sun Yat-sen University (CN), University of Southern Denmark (DK), Shanghai Jiao Tong University (CN), Yonsei University (KR), Vanderbilt University (US), University of Washington (US), Kyoto University (JP), Renji Hospital (CN), Edinburgh Cancer Research (GB), Cleveland Clinic Lerner College of Medicine (US), Institut d'Investigació Biomédica de Bellvitge (ES), National Cancer Center (US), Fred Hutch Cancer Center (US), Chonnam National University Hospital (KR), Korea Health Promotion Institute (KR), Institut Català d'Oncologia (ES), Shanghai Cancer Institute (CN), National Cancer Center (KR), Aichi Cancer Center (JP), State Key Laboratory of Oncogene and Related Genes (CN), Sun Yat-sen University Cancer Center (CN), Chonnam National University Hwasun Hospital (KR), Instituto de Investigación Sanitaria de Santiago (ES), RIKEN Center for Integrative Medical Sciences (JP), Tang Du Hospital (CN), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES), Institute of Genetics and Cancer (GB), University of Virginia (US), Nagoya University (JP), Universitat de Barcelona (ES), The University of Tokyo (JP), University of Birmingham (GB), Universidad de León (ES), Vanderbilt University Medical Center (US), Medical Research Council (GB), University of Edinburgh (GB), Air Force Medical University (CN)
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