Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
J Natl Cancer Inst
; 111(2): 146-157, 2019 02 01.
Article
en En
| MEDLINE
| ID: mdl-29917119
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
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Etnicidad
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Predisposición Genética a la Enfermedad
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Polimorfismo de Nucleótido Simple
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Estudio de Asociación del Genoma Completo
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Sitios Genéticos
Tipo de estudio:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Humans
País/Región como asunto:
America do norte
Idioma:
En
Revista:
J Natl Cancer Inst
Año:
2019
Tipo del documento:
Article