A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood

Abstract

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

Fig. 1. Study organization.

In stage 1, we used the stage 1 dataset to select tuning parameters for PRS construction based on GWAS of BP phenotypes. We compared a few methods for tuning parameter selection and constructed PRSsum combining a few phenotype-specific PRS. In stage 2 we evaluate the methods for tuning parameter selection in the stage 2 dataset, and selected one PRS, namely HTN-PRS, to move forward for two-visit longitudinal analysis. In stage 3, we used a longitudinal dataset from CARDIA to study hypertension development in young adults, and compared Black and White individuals. In stage 4, we tested the association of the HTN-PRS with disease outcomes in MGB biobank (stage 4 dataset).

Fig. 2. Association of PRS with prevalent hypertension at baseline in the stage 2 data set.

Associations of PRS in stage 2 dataset (N = 37,667 individuals). PRS were trained for hypertension association using stage 1 dataset. “Genome-wide significant PRS” are PRS constructed using genome-wide significant SNPs in the discovery GWAS, with fixed LD parameters or R² = 0.1 and distance = 1000 kb. “Selected CV PRS” are PRS that minimized the coefficient of variation (CV) across effect size (log odds ratio (OR)) estimates in 5 independent subsets of the stage 1 dataset. “Selected PVAL-PRS” are PRS that minimized the association p value with hypertension in the stage 1 dataset. Each point provides the estimated OR per 1 standard deviation (SD) increase of the PRS, and error bars represent 95% confidence intervals (CIs). For each PRS association the figure also provides the p value of the estimated association with hypertension based on the Wald test (chi-squared test with one degree of freedom based on two-sided alternative hypothesis), and Area Under the Receiver Operator Curve (AUC). PRS associations were estimated in models adjusted for sex, age, age², study site, race/ethnic background, smoking status, BMI, and 11 ancestral principal components. PRS SDs were defined according to the sampling SDs of the PRS estimated in the entire TOPMed dataset.

Fig. 3. PRS distribution stratified by race/ethnic background.

Density plots showing the distributions of Selected CV-PRS based on each GWAS used (Table 1) and PRSsum constructed by summing Selected CV-PRS from the three GWAS (the final HTN-PRS). The figure was created using the stage 2 dataset. The densities are stratified by race/ethnic background.

Fig. 4. Distribution of longitudinal categories of BP by deciles of the HTN-PRS.

The figure visualizes the distribution of longitudinal BP categories in the stage 2 dataset: hypertension at both exams (treated and/or having hypertension in both exams), worsen (individuals having worse BP category in the follow-up exam compared to the first) improved (individuals having better BP category in the second exam compared to the first, only if they were not treated for hypertension at any point), and no hypertension in both exams (includes normal and elevated BP but without change in category), in deciles of the multi-ethnic HTN-PRS. The numbers provide the sample sizes represented by each bar.

Fig. 5. Association of HTN-PRS with hypertension measures across race/ethnicities.

The forest plot provides the association of the HTN- PRS with prevalent and incident hypertension in the stage 2 dataset, and within race/ethnic backgrounds. The top part corresponds to prevalence analysis at the baseline visit, the middle part corresponds to prediction of new onset hypertension in exam 2, among individuals who had normal BP at baseline, and the bottom part corresponds to prediction of new onset hypertension in exam 2, among individuals who had elevated BP at baseline. For each analysis the figure provides sample size (N), estimated odds ratio (OR) per 1 standard deviation (SD) increase of the PRS, and 95% confidence interval, p value of the association from the Wald test, and area under the receiver operating curve (AUC). Estimated ORs and confidence intervals (CIs) are provided both in the text (left part) and as points and error bars. Heterogeneity of estimated effects across race/ethnic groups was tested using the Cochran’s Q test accounting for correlation due to genetic relatedness across groups. The PRS association was estimated in a model adjusted for sex, age, age², study site, race/ethnic background, smoking status, BMI, and 11 ancestral principal components. PRS SD was defined according to the sampling SD of the PRS estimated in the entire TOPMed dataset. Statistical tests relied on the chi-squared distribution with either one degree of freedom (for effect size estimates) or 4 or 3 degrees of freedom (when testing heterogeneity across 5 or 4 strata of race/ethnic background) based on two-sided alternative hypothesis.

Fig. 6. Trajectories of hypertension risk by strata defined by HTN-PRS in young adults from CARDIA.

Results from analysis of age-dependent risk of hypertension in young adults from CARDIA (stage 3 dataset). We used generalized linear mixed model to model the risk of hypertension by age within strata defined by quantiles of the HTN-PRS. Analyses were adjusted for age, sex and the first 11 PCs of genetic data. Stratification by PRS quantiles was performed in each presented group: All (combined Black and White participants), Black, and White. The effect of age was modeled using a second degree polynomial. At each point on the curve we provide 95% confidence interval of the effect estimate. In the combined sample, all individuals in the top PRS strata are Black, and 99 % of the individuals in the bottom PRS strata are White.

Fig. 7. PRS selection using coefficient of variation workflow.

Flowchart describing the selection of PRS according to the coefficient of variation (CV) criterion. The data set is split into five independent sub-datasets (without related individuals between the subsets). An association model is fit on each sub-dataset for each PRS. Each PRS, defined by a unique combination of tuning parameter, has 5 independent effect size estimates. We compute the CV for each such PRS, and select the PRS that minimizes the CV.