A Self-Adapting Polygenic Risk Score Model Improves Risk Prediction of Venous Thromboembolism in Han Chinese Cohorts.

Most genome-wide association studies (GWAS) of Venous Thromboembolism (VTE) have used data from individuals of European descent, however, genetic factors for VTE have not been fully identified in Chinese populations, which causes the limited use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of VTE for prevention. We, therefore, aimed to curate all the potential VTE-related single-nucleotide polymorphisms (SNPs) for the construction of a new improved PRS model based on the self-adapting method, and then evaluate its utility and effectiveness in the stratification of VTE risk in Chinese populations. We comprehensively analyzed the mutation spectrum of VTE-associated SNPs in the Chinese cohort, and ranked their individual risk effects independently using risk ratio, logistic regression coefficient, and penalty regression coefficient as evaluation criteria. By integrating various algorithms and evaluating their performance, we trained the optimal prediction model of VTE risk in the Chinese population with the least SNP features, established an adaptive PRS model with progressive SNP overlay, and tested it on an independent Chinese population cohort. Self-adaptive polygenic risk score model based on all 318 SNPs or on the 44 most strongly associated SNPs performed similarly (areas under receiver-operating characteristic curves (AUCs) of 0.739 and 0.709, respectively) on the testing dataset of the Chinese VTE cohort, and that achieve the overall best level of the AUC from a conventional PRS model based on known genetic risk factors (0.620-0.718). In addition, we observed the self-adaptive PRS model was an independent effective risk stratification indicator beyond other clinical characteristics including age and smoking status. Our data revealed that only 44 SNPs-derived PRS model can be effectively used in discriminating subpopulations at high risk of VTE. To become clinically useful, our model could benefit from a practically feasible VTE screening program for precision prevention in Chinese populations.

Supplementary information: The online version contains supplementary material available at 10.1007/s43657-024-00192-8.