Novel common genetic susceptibility loci for colorectal cancer

Stephanie L. Schmit, Christopher K. Edlund, Fredrick R. Schumacher, Jian Gong, Tabitha A. Harrison, Jeroen R. Huyghe, Chenxu Qu, Marilena Melas, David J. Van Den Berg, Hansong Wang, Stephanie Tring, Sarah J. Plummer, Demetrius Albanes, M. Henar Alonso, Christopher I. Amos, Kristen Anton, Aaron K. Aragaki, Volker Arndt, Elizabeth L. Barry, Sonja I. BerndtStéphane Bezieau, Stephanie Bien, Amanda Bloomer, Juergen Boehm, Marie Christine Boutron-Ruault, Hermann Brenner, Stefanie Brezina, Daniel D. Buchanan, Katja Butterbach, Bette J. Caan, Peter T. Campbell, Christopher S. Carlson, Jose E. Castelao, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Iona Cheng, Ya Wen Cheng, Lee Soo Chin, James M. Church, Timothy Church, Gerhard A. Coetzee, Michelle Cotterchio, Marcia Cruz Correa, Keith R. Curtis, David Duggan, Douglas F. Easton, Dallas English, Edith J.M. Feskens, Rocky Fischer, Liesel M. FitzGerald, Barbara K. Fortini, Lars G. Fritsche, Charles S. Fuchs, Manuela Gago-Dominguez, Manish Gala, Steven J. Gallinger, W. James Gauderman, Graham G. Giles, Edward L. Giovannucci, Stephanie M. Gogarten, Clicerio Gonzalez-Villalpando, Elena M. Gonzalez-Villalpando, William M. Grady, Joel K. Greenson, Andrea Gsur, Marc Gunter, Christopher A. Haiman, Jochen Hampe, Sophia Harlid, John F. Harju, Richard B. Hayes, Philipp Hofer, Michael Hoffmeister, John L. Hopper, Shu Chen Huang, Jose Maria Huerta, Thomas J. Hudson, David J. Hunter, Gregory E. Idos, Motoki Iwasaki, Rebecca D. Jackson, Eric J. Jacobs, Sun Ha Jee, Mark A. Jenkins, Wei Hua Jia, Shuo Jiao, Amit D. Joshi, Laurence N. Kolonel, Suminori Kono, Charles Kooperberg, Vittorio Krogh, Tilman Kuehn, Sébastien Küry, Andrea LaCroix, Cecelia A. Laurie, Flavio Lejbkowicz, Mathieu Lemire, Heinz Josef Lenz, David Levine, Christopher I. Li, Li Li, Wolfgang Lieb, Yi Lin, Noralane M. Lindor, Yun Ru Liu, Fotios Loupakis, Yingchang Lu, Frank Luh, Jing Ma, Christoph Mancao, Frank J. Manion, Sanford D. Markowitz, Vicente Martin, Koichi Matsuda, Keitaro Matsuo, Kevin J. McDonnell, Caroline E. McNeil, Roger Milne, Antonio J. Molina, Bhramar Mukherjee, Neil Murphy, Polly A. Newcomb, Kenneth Offit, Hanane Omichessan, Domenico Palli, Jesus P. Paredes Cotoré, Julyann Pérez-Mayoral, Paul D. Pharoah, John D. Potter, Conghui Qu, Leon Raskin, Gad Rennert, Hedy S. Rennert, Bridget M. Riggs, Clemens Schafmayer, Robert E. Schoen, Thomas A. Sellers, Daniela Seminara, Gianluca Severi, Wei Shi, David Shibata, Xiao Ou Shu, Erin M. Siegel, Martha L. Slattery, Melissa Southey, Zsofia K. Stadler, Mariana C. Stern, Sebastian Stintzing, Darin Taverna, Stephen N. Thibodeau, Duncan C. Thomas, Antonia Trichopoulou, Shoichiro Tsugane, Cornelia M. Ulrich, Franzel J.B. Van Duijnhoven, Bethany Van Guelpan, Joseph Vijai, Jarmo Virtamo, Stephanie J. Weinstein, Emily White, Aung Ko Win, Alicja Wolk, Michael Woods, Anna H. Wu, Kana Wu, Yong Bing Xiang, Yun Yen, Brent W. Zanke, Yi Xin Zeng, Ben Zhang, Niha Zubair, Sun Seog Kweon, Jane C. Figueiredo, Wei Zheng, Loic Le Marchand, Annika Lindblom, Victor Moreno, Ulrike Peters, Graham Casey, Li Hsu, David V. Conti, Stephen B. Gruber

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Abstract

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Original languageEnglish (US)
Pages (from-to)146-157
Number of pages12
JournalJournal of the National Cancer Institute
Volume111
Issue number2
DOIs
StatePublished - 2019

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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    Schmit, S. L., Edlund, C. K., Schumacher, F. R., Gong, J., Harrison, T. A., Huyghe, J. R., Qu, C., Melas, M., Van Den Berg, D. J., Wang, H., Tring, S., Plummer, S. J., Albanes, D., Alonso, M. H., Amos, C. I., Anton, K., Aragaki, A. K., Arndt, V., Barry, E. L., ... Gruber, S. B. (2019). Novel common genetic susceptibility loci for colorectal cancer. Journal of the National Cancer Institute, 111(2), 146-157. https://doi.org/10.1093/jnci/djy099