Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects

Xingyi Guo*, Weiqiang Lin, Wanqing Wen, Jeroen Huyghe, Stephanie Bien, Qiuyin Cai, Tabitha Harrison, Zhishan Chen, Conghui Qu, Jiandong Bao, Jirong Long, Yuan Yuan, Fangqin Wang, Mengqiu Bai, Goncalo R. Abecasis, Demetrius Albanes, Sonja I. Berndt, Stéphane Bézieau, D.T. Bishop, Hermann BrennerStephan Buch, Andrea Burnett-Hartman, Peter T. Campbell, Sergi Castellví-Bel, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Sang Hee Cho, David V. Conti, Albert de la Chapelle, Edith J.M. Feskens, Steven J. Gallinger, Graham G. Giles, Phyllis J. Goodman, Andrea Gsur, Mark Guinter, Marc J. Gunter, Jochen Hampe, Heather Hampel, Richard B. Hayes, Michael Hoffmeister, Ellen Kampman, Hyun Min Kang, Temitope O. Keku, Hyeong Rok Kim, Loic Le Marchand, Soo Chin Lee, Christopher I. Li, Li Li, Annika Lindblom, Noralane Lindor, Roger L. Milne, Victor Moreno, Neil Murphy, Polly A. Newcomb, Deborah A. Nickerson, Kenneth Offit, Rachel Pearlman, Paul D.P. Pharoah, Elizabeth A. Platz, John D. Potter, Gad Rennert, Lori C. Sakoda, Clemens Schafmayer, Stephanie L. Schmit, Robert E. Schoen, Fredrick R. Schumacher, Martha L. Slattery, Yu Ru Su, Catherine M. Tangen, Cornelia M. Ulrich, Franzel J.B. van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Xiaoliang Wang, Emily White, Alicja Wolk, Michael O. Woods, Graham Casey, Li Hsu, Mark A. Jenkins, Stephen B. Gruber, Ulrike Peters, Wei Zheng

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background And Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10–6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P <.01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

Original languageEnglish
Pages (from-to)1-21
JournalGastroenterology
DOIs
Publication statusE-pub ahead of print - 12 Oct 2021

Keywords

  • CABLES2.
  • Colorectal Cancer
  • Susceptibility Genes
  • TWAS

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