Table 1.
Best-performing polygenic risk scores and testing for associations with measured lipid traits
| Polygenic risk score | Lipid trait | No. of SNPs | Derivation strategy and tuning parameter | Cohort | n | Correlation with lipid trait | Linear regression | Proportion of variance | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pearson r | Spearman r | β | SE | P | PQ | explained by polygenic risk score | ||||||
| PRSTC | TC | 229 | Pruning and thresholding | Children | 909 | 0.299 | 0.295 | 0.050 | 0.005 | 2.2 × 10−21 | – | 9.49% |
| (r2 = 0.2 and p = 10− 5) | Adolescents | 1973 | 0.327 | 0.322 | 0.056 | 0.004 | 8.9 × 10− 53 | – | 10.93% | |||
| Healthy adults | 441 | 0.334 | 0.320 | 0.057 | 0.008 | 2.2 × 10−13 | – | 10.07% | ||||
| Adult women | 948 | 0.243 | 0.259 | 0.042 | 0.005 | 3.2 × 10−16 | – | 6.26% | ||||
| Combined analysis in validation dataset | 4271 | 0.304 | 0.302 | 0.052 | 0.002 | 7.5 × 10−103 | 0.1197 | – | ||||
| Adults | 426 | 0.251 | 0.263 | 0.043 | 0.008 | 2.9 × 10−7 | – | 5.06% | ||||
| T2D patients in HKDR study | 4917 | 0.186 | 0.199 | 0.042 | 0.003 | 3.7 × 10−45 | – | 3.93% | ||||
| T2D patients in HKDB phase 1 study | 1941 | 0.187 | 0.186 | 0.036 | 0.004 | 2.3 × 10−16 | – | 3.32% | ||||
| T2D patients in HKDB phase 2 study | 865 | 0.173 | 0.176 | 0.034 | 0.006 | 1.8 × 10−7 | – | 2.98% | ||||
| Combined analysis in T2D patients | 7723 | 0.185 | 0.193 | 0.039 | 0.002 | 1.5 × 10−66 | 0.3721 | – | ||||
| PRSTG | TG | 142 | Pruning and thresholding | Children | 909 | 0.243 | 0.245 | 0.106 | 0.012 | 3.7 × 10−17 | – | 7.19% |
| (r2 = 0.2 and p = 5 × 10−8) | Adolescents | 1973 | 0.244 | 0.227 | 0.097 | 0.008 | 3.4 × 10−30 | – | 5.99% | |||
| Healthy adults | 441 | 0.257 | 0.245 | 0.139 | 0.022 | 9.5 × 10−10 | – | 5.59% | ||||
| Adult women | 948 | 0.294 | 0.256 | 0.146 | 0.015 | 9.9 × 10−23 | – | 8.59% | ||||
| Combined analysis in validation dataset | 4271 | 0.256 | 0.239 | 0.111 | 0.006 | 1.3 × 10−75 | 0.0150 | – | ||||
| Adults | 426 | 0.251 | 0.230 | 0.133 | 0.023 | 1.7 × 10−8 | – | 5.14% | ||||
| T2D patients in HKDR study | 4917 | 0.200 | 0.251 | 0.165 | 0.008 | 1.3 × 10−87 | – | 7.31% | ||||
| T2D patients in HKDB phase 1 study | 1941 | 0.209 | 0.191 | 0.133 | 0.013 | 1.6 × 10−25 | – | 5.00% | ||||
| T2D patients in HKDB phase 2 study | 865 | 0.231 | 0.197 | 0.140 | 0.019 | 2.8 × 10−13 | – | 5.58% | ||||
| Combined analysis in T2D patients | 7723 | 0.206 | 0.230 | 0.154 | 0.006 | 2.3 × 10−126 | 0.0721 | – | ||||
| PRSHDL | HDL-C | 549 | Pruning and thresholding | Children | 909 | 0.263 | 0.250 | 0.052 | 0.007 | 4.0 × 10−15 | – | 6.37% |
| (r2 = 0.2 and p = 10−4) | Adolescents | 1973 | 0.281 | 0.258 | 0.054 | 0.004 | 4.0 × 10− 38 | – | 7.27% | |||
| Healthy adults | 441 | 0.347 | 0.313 | 0.084 | 0.010 | 4.0 × 10−15 | – | 9.44% | ||||
| Adult women | 948 | 0.271 | 0.257 | 0.058 | 0.007 | 1.7 × 10−17 | – | 6.35% | ||||
| Combined analysis in validation dataset | 4271 | 0.282 | 0.262 | 0.057 | 0.003 | 9.3 × 10−83 | 0.0458 | – | ||||
| Adults | 426 | 0.272 | 0.269 | 0.066 | 0.012 | 2.3 × 10−8 | – | 5.58% | ||||
| T2D patients in HKDR study | 4917 | 0.222 | 0.226 | 0.064 | 0.004 | 7.4 × 10−64 | – | 5.24% | ||||
| T2D patients in HKDB phase 1 study | 1941 | 0.239 | 0.237 | 0.073 | 0.006 | 8.6 × 10−32 | – | 6.06% | ||||
| T2D patients in HKDB phase 2 study | 865 | 0.267 | 0.252 | 0.077 | 0.008 | 6.1 × 10−21 | – | 8.27% | ||||
| Combined analysis in T2D patients | 7723 | 0.231 | 0.232 | 0.068 | 0.003 | 3.2 × 10− 116 | 0.1906 | – | ||||
| PRSLDL | LDL-C | 84 | Pruning and thresholding | Children | 909 | 0.239 | 0.243 | 0.068 | 0.008 | 1.1 × 10−15 | – | 6.81% |
| (r2 = 0.2 and p = 5 × 10−8) | Adolescents | 1973 | 0.309 | 0.294 | 0.093 | 0.006 | 2.6 × 10−53 | – | 10.88% | |||
| Healthy adults | 441 | 0.274 | 0.274 | 0.077 | 0.012 | 9.8 × 10−10 | – | 7.22% | ||||
| Adult women | 948 | 0.262 | 0.275 | 0.071 | 0.008 | 1.0 × 10−16 | – | 6.33% | ||||
| Combined analysis in validation dataset | 4271 | 0.281 | 0.277 | 0.081 | 0.004 | 2.4 × 10−93 | 0.0439 | – | ||||
| Adults | 426 | 0.255 | 0.288 | 0.072 | 0.012 | 5.8 × 10−9 | – | 6.72% | ||||
| T2D patients in HKDR study | 4917 | 0.178 | 0.175 | 0.059 | 0.004 | 1.8 × 10−38 | – | 3.51% | ||||
| T2D patients in HKDB phase 1 study | 1941 | 0.190 | 0.175 | 0.054 | 0.006 | 3.0 × 10−17 | – | 3.60% | ||||
| T2D patients in HKDB phase 2 study | 865 | 0.195 | 0.171 | 0.058 | 0.010 | 9.2 × 10−9 | – | 3.74% | ||||
| Combined analysis in T2D patients | 7723 | 0.183 | 0.175 | 0.057 | 0.003 | 3.2 × 10−62 | 0.8303 | – | ||||
The optimal polygenic risk scores for four lipid traits were chosen based on the validation datasets which consisted of 909 children, 1973 adolescents, 441 health adults, and 948 adult women. These scores were further tested in 426 adults from the general population and 7723 individuals from three cohorts of T2D patients. Associations between polygenic risk scores and lipid traits were assessed by Pearson and Spearman correlations and a linear regression model. Within individual cohorts, p values were obtained from linear regression with adjustment of principal components, sex, age, and body mass index. Lipid traits were natural log-transformed for the linear regression analysis. Results from cohorts of children, adolescents, healthy adults, and adult women were meta-analyzed using a fixed effects model in the validation stage (n = 4271), while results from three cohorts of T2D patients were combined in the testing stage (n = 7723). PQ refers to the p value of Cochran’s Q-statistics in heterogeneity test. The proportion of variance for a lipid trait explained by the corresponding optimal PRS was computed as the R2 obtained from a full model including both PRS and covariates (PCs, sex, age, and BMI) minus the R2 obtained from a model including covariates alone