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

Nature communications 2026 Vol.17(1) p. 1377

Chen Z, Song W, Li Q, Li C, Wen W, Huyghe JR, Law PJ, Fernandez-Rozadilla C, Timofeeva MN, Thomas M, Schmit SL, Martin V, Devall M, Dampier C, Moratalla-Navarro F, Cai Q, Wang J, Shi J, Kweon SS, Tanikawa C, Jia WH, Shu X, Long J, Gao J, Kim J, Shin A, Matsuo K, Jee SH, Jung KJ, Wang N, Kim DH, Ping J, Yang G, Shin MH, Ren Z, Oh JH, Oze I, Ahn YO, Gao YT, Pan ZZ, Kamatani Y, Van Kaer L, Wu L, Li B, Matsuda K, Shu XO, Hsu L, Dunlop MG, Gruber SB, Houlston R, Tomlinson I, Li L, Lau KS, Moreno V, Casey G, Peters U, Zheng W, Guo X

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Susceptibility transcription factors (TF) whose DNA bindings are altered by genetic variants regulating colorectal cancer (CRC) risk genes remain poorly defined.

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BibTeX ↓ RIS ↓
APA Chen Z, Song W, et al. (2026). Mixed-model and transcriptome-wide association analyses identify transcription factors and genes associated with colorectal cancer susceptibility.. Nature communications, 17(1), 1377. https://doi.org/10.1038/s41467-025-68127-z
MLA Chen Z, et al.. "Mixed-model and transcriptome-wide association analyses identify transcription factors and genes associated with colorectal cancer susceptibility.." Nature communications, vol. 17, no. 1, 2026, pp. 1377.
PMID 41540004
DOI 10.1038/s41467-025-68127-z

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.

MeSH Terms

Humans; Colorectal Neoplasms; Genome-Wide Association Study; Genetic Predisposition to Disease; Transcription Factors; Gene Expression Regulation, Neoplastic; Transcriptome; Gene Regulatory Networks; Polymorphism, Single Nucleotide; Asian People; White People; Gene Expression Profiling; Female; Alternative Splicing; Male

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