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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; [...]

Novel Common Genetic Susceptibility Loci for Colorectal Cancer

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  • Medientyp: E-Artikel
  • Titel: Novel Common Genetic Susceptibility Loci for Colorectal Cancer
  • Beteiligte: 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; [...]
  • Erschienen: Oxford University Press (OUP), 2019
  • Erschienen in: JNCI: Journal of the National Cancer Institute
  • Sprache: Englisch
  • DOI: 10.1093/jnci/djy099
  • ISSN: 0027-8874; 1460-2105
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Previous genome-wide association studies (GWAS) have identified 42 loci (P &lt; 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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 &lt; 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>The discovery GWAS identified 11 variants associated with CRC at P &lt; 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.</jats:p> </jats:sec>
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