BACKGROUND: The clinical utility of personal genomic information in identifying individuals at increased risks for dyslipidemia and cardiovascular diseases remains unclear. METHODS: We used data from Biobank Japan (n = 70,657-128,305) and developed novel East Asian-specific genome-wide polygenic risk scores (PRSs) for four lipid traits. We validated (n = 4271) and subsequently tested associations of these scores with 3-year lipid changes in adolescents (n = 620), carotid intima-media thickness (cIMT) in adult women (n = 781), dyslipidemia (n = 7723), and coronary heart disease (CHD) (n = 2374 cases and 6246 controls) in type 2 diabetes (T2D) patients. RESULTS: Our PRSs aggregating 84-549 genetic variants (0.251 < correlation coefficients (r) < 0.272) had comparably stronger association with lipid variations than the typical PRSs derived based on the genome-wide significant variants (0.089 < r < 0.240). Our PRSs were robustly associated with their corresponding lipid levels (7.5 × 10 < P < 1.3 × 10) and 3-year lipid changes (1.4 × 10 < P < 0.0130) which started to emerge in childhood and adolescence. With the adjustments for principal components (PCs), sex, age, and body mass index, there was an elevation of 5.3% in TC (β ± SE = 0.052 ± 0.002), 11.7% in TG (β ± SE = 0.111 ± 0.006), 5.8% in HDL-C (β ± SE = 0.057 ± 0.003), and 8.4% in LDL-C (β ± SE = 0.081 ± 0.004) per one standard deviation increase in the corresponding PRS. However, their predictive power was attenuated in T2D patients (0.183 < r < 0.231). When we included each PRS (for TC, TG, and LDL-C) in addition to the clinical factors and PCs, the AUC for dyslipidemia was significantly increased by 0.032-0.057 in the general population (7.5 × 10 < P < 0.0400) and 0.029-0.069 in T2D patients (2.1 × 10 < P < 0.0428). Moreover, the quintile of TC-related PRS was moderately associated with cIMT in adult women (β ± SE = 0.011 ± 0.005, P = 0.0182). Independent of conventional risk factors, the quintile of PRSs for TC [OR (95% CI) = 1.07 (1.03-1.11)], TG [OR (95% CI) = 1.05 (1.01-1.09)], and LDL-C [OR (95% CI) = 1.05 (1.01-1.09)] were significantly associated with increased risk of CHD in T2D patients (4.8 × 10 < P < 0.0197). Further adjustment for baseline lipid drug use notably attenuated the CHD association. CONCLUSIONS: The PRSs derived and validated here highlight the potential for early genomic screening and personalized risk assessment for cardiovascular disease.