Abstract
<jats:p>Background and objective: Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide. Early identification of high-risk individuals allows targeted prevention and early detection. Design: We constructed a polygenic risk score (PRS) for CRC risk using data from 1,448,354 individuals (103,401 cases). We evaluated its performance for identifying high-risk individuals in 6 major ancestries. Results: The PRS was strongly associated with CRC risk in Europeans (OR per SD =2.13, 95%CI=1.98-2.28), Africans (OR=1.35, 95%CI=1.11-1.64), Hispanics (OR=1.97, 95%CI =1.48-2.61), East Asians (OR=1.98, 95%CI=1.35-2.91), South Asians (OR=1.85, 95%CI=1.44 -2.37), and Middle Easterners (OR=3.10, 95%CI=1.38-6.95). Europeans in the top 10% genetic risk had 14-fold and 5-fold higher CRC risks compared to the bottom 10% (OR=13.50, 95%CI=8.67-21.00), and average (20-70%) risk groups (OR=4.64, 95%CI=3.89-5.52), respectively. The CRC risk in the top 10% individuals was equivalent to having three affected first degree relatives with CRC diagnosed at any age. Genetically high-risk individuals developed CRC up to 15 years earlier than the average. The PRS was strongly associated with early onset CRC risk e.g. in AFR (OR=3.22, 95%CI=1.79-5.81), and improved its prediction e.g. by 9% beyond clinical predictors in EUR. Conclusion: A comprehensive genetic prediction of CRC risk provides insights that could streamline screening and prevention guidelines.</jats:p>