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

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

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
Pages (from-to)146-157
Number of pages12
JournalJournal of the National Cancer Institute
Volume111
Issue number2
Early online date16 Jun 2018
DOIs
Publication statusPublished - 01 Feb 2019

Bibliographical note

© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Keywords

  • Case-Control Studies
  • Colorectal Neoplasms/epidemiology
  • Ethnic Groups/genetics
  • Follow-Up Studies
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Polymorphism, Single Nucleotide
  • Prognosis
  • United States/epidemiology

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