Background: Inherited susceptibility is an important contributor single variant analysis. Pathway-level association analyses based to colorectal cancer risk, and rare variants in key genes or pathways on the integrative BRI (iBRI) method found extreme evidence of could account in part for the missing proportion of colorectal cancer association with the DNA repair pathway (BFiBRI = 17852.4), heritability. specifically with the nonhomologous end joining (BFiBRI = Methods: We conducted an exome-wide association study 437.95) and nucleotide excision repair (BFiBRI = 36.96) subpathincluding 2,327 cases and 2,966 controls of European ancestry from ways. The iBRI method also identified RPA2, PRKDC, ERCC5, three large epidemiologic studies. Single variant associations were and ERCC8 as the top associated DNA repair genes (summary tested using logistic regression models, adjusting for appropriate BFiBRI ≥ 10), with rs28988897, rs8178232, rs141369732, and study-specific covariates. In addition, we examined the aggregate rs201642761 being the most likely associated variants in these effects of rare coding variation at the gene and pathway levels using genes, respectively. Bayesian model uncertainty techniques. Conclusions: We identified novel variants and genes associated Results: In an exome-wide gene-level analysis, we identified with colorectal cancer risk and provided additional evidence for a ST6GALNAC2 as the top associated gene based on the Bayesian role of DNA repair in colorectal cancer tumorigenesis. risk index (BRI) method [summary Bayes factor (BF)BRI = Impact: This study provides new insights into the genetic 2604.23]. A rare coding variant in this gene, rs139401613, was predisposition to colorectal cancer, which has potential for trans-the top associated variant (P = 1.01 × 10–6) in an exome-wide lation into improved risk prediction.
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