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, Yi Lin, Yun Ru Liu, Yun Yen, Li Hsu

研究成果: 雜誌貢獻文章

27 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)146-157
頁數12
期刊Journal of the National Cancer Institute
111
發行號2
DOIs
出版狀態已發佈 - 二月 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    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., ... Hsu, L. (2019). Novel Common Genetic Susceptibility Loci for Colorectal Cancer. Journal of the National Cancer Institute, 111(2), 146-157. https://doi.org/10.1093/jnci/djy099