Background
Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide. Early identification of individuals at highest risk is a public health need.
Methods
We constructed a genome-wide polygenic risk score (PRS) for CRC risk using data from 1,448,354 individuals (103,401 cases). We evaluated its performance to identify high risk individuals in 6 major ancestral populations.
Results
The PRS was strongly associated with CRC risk across different ancestries; e.g. Europeans (OR per SD =2.03, 95%CI=1.89-2.18, Africans (OR=1.32, 95%CI=1.09-1.60), Hispanics (OR=1.89, 95%CI=1.43-2.50), East Asians (OR=2.24, 95%CI=1.53-3.27), South Asians (OR=1.78, 95% CI=1.39-2.28), and Middle Easterners (OR= 3.10, 95% CI = 1.38 - 6.95). It identified individuals with a high genetic risk whose risk of developing CRC was 14 and 5 times higher than those with low and average genetic risk respectively (OR = 13.50, 95%CI=8.67 - 21.00 and OR=4.64, 95%CI=3.89-5.52). Genetically high risk individuals were likely to develop CRC 15 years earlier than the average. The PRS was strongly associated with early onset CRC (EOCRC) risk e.g. in AFR (OR=3.22, 95%CI=1.79-5.81). Genetically high-risk younger individuals had a 6-fold increased risk of EORC compared to the average (OR=5.99, 95%CI=2.97-12.09). The PRS improved identification of high risk individuals by 7%, and 9% for “any age” CRC and EOCRC respectively, over and above clinical predictors.
Conclusion
We provide comprehensive evidence to support potential integration of genetic screening for CRC into clinical practice guidelines for prevention, screening and, early identification and prevention.