Novel Common Genetic Susceptibility Loci for Colorectal Cancer
Authors: Schmit, SL; Edlund, CK; Schumacher, FR; Gong, J; Harrison, TA; Huyghe, , JR; Qu, C; Melas, M; Van Den Berg, DJ; Wang, H; Tring, S; Plummer, SJ; Albanes, D; Alonso, MH; Amos, CI; Anton, K; Aragaki, AK; Arndt, V; Barry, EL; Berndt, SI; Bezieau, S; Bien, S; Bloomer, A; Boehm, J; Boutron-Ruault, MC; Brenner, H; Brezina, S; Buchanan, DD; Butterbach, K; Caan, BJ; Campbell, PT; Carlson, CS; Castelao, JE; Chan, AT; Chang-Claude, J; Chanock, SJ; Cheng, I; Cheng, YW; Chin, LS; Church, JM; Church, T; Coetzee, GA; Cotterchio, M; Cruz Correa, M; Curtis, KR; Duggan, D; Easton, DF; English, D; Feskens, EJM; Fischer, R; Fitzgerald, LM; Fortini, BK; Fritsche, LG; Fuchs, CS; Gago-Dominguez, M; Gala, M; Gallinger, SJ; Gauderman, WJ; Giles, GG; Giovannucci, EL; Gogarten, SM; Gonzalez-Villalpando, C; Gonzalez-Villalpando, EM; Grady, WM; Greenson, JK; Gsur, A; Gunter, M; Haiman, CA; Hampe, J; Harlid, S; Harju, JF; Hayes, RB; Hofer, P; Hoffmeister, M; Hopper, JL; Huang, SC; Huerta, JM; Hudson, TJ; Hunter, DJ; Idos, GE; Iwasaki, M; Jackson, RD; Jacobs, EJ; Jee, SH; Jenkins, MA; Jia, WH; Jiao, S; Joshi, AD; Kolonel, LN; Kono, S; Kooperberg, C; Krogh, V; Kuehn, T; Küry, S; Lacroix, A; Laurie, CA; Lejbkowicz, F; Lemire, M; Lenz, HJ; Levine, D; Li, CI; Li, L; Lieb, W; Lin, Y; Lindor, NM; Liu, YR; Loupakis, F; Lu, Y; Luh, F; Ma, J; Mancao, C; Manion, FJ; Markowitz, SD; Martin, V; Matsuda, K; Matsuo, K; Mcdonnell, KJ; Mcneil, CE; Milne, R; Molina, AJ; Mukherjee, B; Murphy, N; Newcomb, PA; Offit, K; Omichessan, H; Palli, D; Cotoré, JPP; Pérez-Mayoral, J; Pharoah, PD; Potter, JD; Qu, C; Raskin, L; Rennert, G; Rennert, HS; Riggs, BM; Schafmayer, C; Schoen, RE; Sellers, TA; Seminara, D; Severi, G; Shi, W; Shibata, D; Shu, XO; Siegel, EM; Slattery, ML; Southey, M; Stadler, ZK; Stern, MC; Stintzing, S; Taverna, D; Thibodeau, SN; Thomas, DC; Trichopoulou, A; Tsugane, S; Ulrich, CM; van Duijnhoven, FJB; van Guelpan, B; Vijai, J; Virtamo, J; Weinstein, SJ; White, E; Win, AK; Wolk, A; Woods, M; Wu, AH; Wu, K; Xiang, YB; Yen, Y; Zanke, BW; Zeng, YX; Zhang, B; Zubair, N; Kweon, SS; Figueiredo, JC; Zheng, W; Marchand, LL; Lindblom, A; Moreno, V; Peters, U; Casey, G; Hsu, L; Conti, DV; Gruber, SB
HERO ID: 5882806
BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci . . .
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.