Novel Common Genetic Susceptibility Loci for Colorectal Cancer
Stephanie Schmit, Christopher Edlund, Fredrick Schumacher, Jian Gong, Tabitha Harrison, Jeroen Huyghe, Chenxu Qu, Marilena Melas, David van den Berg, Hansong Wang, Stephanie Tring, Sarah Plummer, Demetrius Albanes, M. Alonso, Christopher Amos, Kristen Anton, Aaron Aragaki, Volker Arndt, Elizabeth Barry, Sonja Berndt, Stephane Bezieau, Stephanie Bien, Amanda Bloomer, Juergen Boehm, Marie-Christine Boutron-Ruault, Hermann Brenner, Stefanie Brezina, Daniel Buchanan, Katja Butterbach, Bette Caan, Peter Campbell, Christopher Carlson, Jose Castelao, Andrew Chan, Jenny Chang-Claude, Stephen Chanock, Iona Cheng, Ya-Wen Cheng, Lee Chin, James Church, Timothy Church, Gerhard Coetzee, Michelle Cotterchio, Marcia Cruz Correa, Keith Curtis, David Duggan, Douglas Easton, Dallas English, Edith Feskens, Rocky Fischer, Liesel FitzGerald, Barbara Fortini, Lars Fritsche, Charles Fuchs, Manuela Gago-Dominguez, Manish Gala, Steven Gallinger, W. Gauderman, Graham Giles, Edward Giovannucci, Stephanie Gogarten, Clicerio Gonzalez-Villalpando, Elena Gonzalez-Villalpando, William Grady, Joel Greenson, Andrea Gsur, Marc Gunter, Christopher Haiman, Jochen Hampe, Sophia Harlid, John Harju, Richard Hayes, Philipp Hofer, Michael Hoffmeister, John Hopper, Shu-Chen Huang, Jose Huerta, Thomas Hudson, David Hunter, Gregory Idos, Motoki Iwasaki, Rebecca Jackson, Eric Jacobs, Sun Jee, Mark Jenkins, Wei-Hua Jia, Shuo Jiao, Amit Joshi, Laurence Kolonel, Suminori Kono, Charles Kooperberg, Vittorio Krogh, Tilman Kuehn, Sebastien Kury, Andrea LaCroix, Cecelia Laurie, Flavio Lejbkowicz, Mathieu Lemire, Heinz-Josef Lenz, David Levine, Christopher Li, Li Li, Wolfgang Lieb, Yi Lin, Noralane Lindor, Yun-Ru Liu, Fotios Loupakis, Yingchang Lu, Frank Luh, Jing Ma, Christoph Mancao, Frank Manion, Sanford Markowitz, Vicente Martin, Koichi Matsuda, Keitaro Matsuo, Kevin McDonnell, Caroline McNeil, Roger Milne, Antonio Molina, Bhramar Mukherjee, Neil Murphy, Polly Newcomb, Kenneth Offit, Hanane Omichessan, Domenico Palli, Jesus Cotore, Julyann Perez-Mayoral, Paul Pharoah, John Potter, Conghui Qu, Leon Raskin, Gad Rennert, Hedy Rennert, Bridget Riggs, Clemens Schafmayer, Robert Schoen, Thomas Sellers, Daniela Seminara, Gianluca Severi, Wei Shi, David Shibata, Xiao-Ou Shu, Erin Siegel, Martha Slattery, Melissa Southey, Zsofia Stadler, Mariana Stern, Sebastian Stintzing, Darin Taverna, Stephen Thibodeau, Duncan Thomas, Antonia Trichopoulou, Shoichiro Tsugane, Cornelia Ulrich, Franzel van Duijnhoven, Bethany van Guelpan, Joseph Vijai, Jarmo Virtamo, Stephanie Weinstein, Emily White, Aung Win, Alicja Wolk, Michael Woods, Anna Wu, Kana Wu, Yong-Bing Xiang, Yun Yen, Brent Zanke, Yi-Xin Zeng, Ben Zhang, Niha Zubair, Sun-Seog Kweon, Jane Figueiredo, Wei Zheng, Loic Le Marchand, Annika Lindblom, Victor Moreno, Ulrike Peters, Graham Casey, Li Hsu, David Conti, Stephen Gruber
Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 x 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 x 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 x 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.