Novel common genetic susceptibility loci for colorectal cancer Journal Article
| Authors: | Schmit, S. L.; Edlund, C. K.; Schumacher, F. R.; Gong, J.; Harrison, T. A.; Huyghe, J. R.; Qu, C.; Melas, M.; Van Den Berg, D. J.; Wang, H.; Tring, S.; Plummer, S. J.; Albanes, D.; Alonso, M. H.; Amos, C. I.; Anton, K.; Aragaki, A. K.; Arndt, V.; Barry, E. L.; Berndt, S. I.; Bezieau, S.; Bien, S.; Bloomer, A.; Boehm, J.; Boutron-Ruault, M. C.; Brenner, H.; Brezina, S.; Buchanan, D. D.; Butterbach, K.; Caan, B. J.; Campbell, P. T.; Carlson, C. S.; Castelao, J. E.; Chan, A. T.; Chang-Claude, J.; Chanock, S. J.; Cheng, I.; Cheng, Y. W.; Chin, L. S.; Church, J. M.; Church, T.; Coetzee, G. A.; Cotterchio, M.; Cruz Correa, M.; Curtis, K. R.; Duggan, D.; Easton, D. F.; English, D.; Feskens, E. J. M.; Fischer, R.; FitzGerald, L. M.; Fortini, B. K.; Fritsche, L. G.; Fuchs, C. S.; Gago-Dominguez, M.; Gala, M.; Gallinger, S. J.; Gauderman, W. J.; Giles, G. G.; Giovannucci, E. L.; Gogarten, S. M.; Gonzalez-Villalpando, C.; Gonzalez-Villalpando, E. M.; Grady, W. M.; Greenson, J. K.; Gsur, A.; Gunter, M.; Haiman, C. A.; Hampe, J.; Harlid, S.; Harju, J. F.; Hayes, R. B.; Hofer, P.; Hoffmeister, M.; Hopper, J. L.; Huang, S. C.; Huerta, J. M.; Hudson, T. J.; Hunter, D. J.; Idos, G. E.; Iwasaki, M.; Jackson, R. D.; Jacobs, E. J.; Jee, S. H.; Jenkins, M. A.; Jia, W. H.; Jiao, S.; Joshi, A. D.; Kolonel, L. N.; Kono, S.; Kooperberg, C.; Krogh, V.; Kuehn, T.; Küry, S.; LaCroix, A.; Laurie, C. A.; Lejbkowicz, F.; Lemire, M.; Lenz, H. J.; Levine, D.; Li, C. I.; Li, L.; Lieb, W.; Lin, Y.; Lindor, N. M.; Liu, Y. R.; Loupakis, F.; Lu, Y.; Luh, F.; Ma, J.; Mancao, C.; Manion, F. J.; Markowitz, S. D.; Martin, V.; Matsuda, K.; Matsuo, K.; McDonnell, K. J.; McNeil, C. E.; Milne, R.; Molina, A. J.; Mukherjee, B.; Murphy, N.; Newcomb, P. A.; Offit, K.; Omichessan, H.; Palli, D.; Cotoré, J. P. P.; Pérez-Mayoral, J.; Pharoah, P. D.; Potter, J. D.; Qu, C.; Raskin, L.; Rennert, G.; Rennert, H. S.; Riggs, B. M.; Schafmayer, C.; Schoen, R. E.; Sellers, T. A.; Seminara, D.; Severi, G.; Shi, W.; Shibata, D.; Shu, X. O.; Siegel, E. M.; Slattery, M. L.; Southey, M.; Stadler, Z. K.; Stern, M. C.; Stintzing, S.; Taverna, D.; Thibodeau, S. N.; Thomas, D. C.; Trichopoulou, A.; Tsugane, S.; Ulrich, C. M.; van Duijnhoven, F. J. B.; van Guelpan, B.; Vijai, J.; Virtamo, J.; Weinstein, S. J.; White, E.; Win, A. K.; Wolk, A.; Woods, M.; Wu, A. H.; Wu, K.; Xiang, Y. B.; Yen, Y.; Zanke, B. W.; Zeng, Y. X.; Zhang, B.; Zubair, N.; Kweon, S. S.; Figueiredo, J. C.; Zheng, W.; Marchand, L. L.; Lindblom, A.; Moreno, V.; Peters, U.; Casey, G.; Hsu, L.; Conti, D. V.; Gruber, S. B. |
| Article Title: | Novel common genetic susceptibility loci for colorectal cancer |
| 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. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com. |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 111 |
| Issue: | 2 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 2019-02-01 |
| Start Page: | 146 |
| End Page: | 157 |
| Language: | English |
| DOI: | 10.1093/jnci/djy099 |
| PUBMED: | 29917119 |
| PROVIDER: | scopus |
| PMCID: | PMC6555904 |
| DOI/URL: | |
| Notes: | Vijai Joseph's first and last names are reversed on the original publication -- Source: Scopus |
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