Developing and validating polygenic risk scores for colorectal cancer risk prediction in East Asians

Background & Aims: Several polygenic risk scores (PRSs) have been developed to predict the risk of colorectal cancer (CRC) in European descendants. We aimed to develop and validate CRC PRSs for East Asians. Methods: PRSs were developed using genome-wide association study (GWAS) data from 22,702 cases and 212,486 controls and validated in two case-control studies (1,454 Korean and 1,736 Chinese). Eleven PRSs were derived using three approaches: GWAS-identified CRC risk SNPs; CRC risk variants identified through fine-mapping of known risk loci; and genome-wide risk prediction algorithms. Logistic regression models were used to estimate odds ratios (ORs) and area under the receiver operating characteristic curve (AUC). Results: In the validation sets, PRS115-EAS, a PRS with 115 GWAS-reported risk variants derived from East-Asian data performed significantly better than PRS115-EUR, a PRS derived using GWAS data from European descendants. In the Korea validation set, ORs per SD increase of PRS115-EAS were 1.63 (95%CI = 1.46 - 1.82; AUC = 0.63), compared with OR of 1.44 (95%CI = 1.29 - 1.60, AUC = 0.60) for PRS115-EUR, derived using European-ancestry data. PRS115-EAS/EUR derived using meta-analysis results of both populations slightly improved the AUC to 0.64. Similar but weaker associations were found in the China validation set. Individuals among the highest 5% of PRS115-EAS/EUR have a 2.52-fold elevated CRC risk compared with the average risk group and have a 12-20% risk of developing CRC by age 85. Conclusions: CRC PRSs are promising in predicting risk of this cancer in East Asians. Using data from East Asians significantly improves model performance.