A linear weighted combination of polygenic scores for a broad range of traits improves prediction of coronary heart disease

Polygenic scores (PGS) for coronary heart disease (CHD) are constructed using GWAS summary statistics for CHD. However, pleiotropy is pervasive in biology and disease-associated variants often share etiologic pathways with multiple traits. Therefore, incorporating GWAS summary statistics of additional traits could improve the performance of PGS for CHD. Using lasso regression models, we developed two multi-PGS for CHD: 1) multiPGS_CHD, utilizing GWAS summary statistics for CHD, its risk factors, and other ASCVD as training data and the UK Biobank for tuning, and 2) extendedPGS_CHD, using existing PGS for a broader range of traits in the PGS Catalog as training data and the Atherosclerosis Risk in Communities Study (ARIC) cohort for tuning. We evaluated the performance of multiPGS_CHD and extendedPGS_CHD in the Mayo Clinic Biobank, an independent cohort of 43,578 adults of European ancestry which included 4,479 CHD cases and 39,099 controls. In the Mayo Clinic Biobank, a 1 SD increase in multiPGS_CHD and extendedPGS_CHD was associated with a 1.66-fold (95% CI: 1.60-1.71) and 1.70-fold (95% CI: 1.64-1.76) increased odds of CHD, respectively, in models that included age, sex, and 10 PCs, whereas an already published PGS for CHD (CHD_PRSCS) increased the odds by 1.50 (95% CI: 1.45-1.56). In the highest deciles of extendedPGS_CHD, multiPGS_CHD, and CHD_PRSCS, 18.4%, 17.5%, and 16.3% of patients had CHD, respectively.