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, Stephane; 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 | Abstract: Background:Previous genome-wide association studies (GWAS) have identified 42 loci (P l 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 l 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 l 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.