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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

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

Published Web Location

https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djy099/5039592
No data is associated with this publication.
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.

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