Pathway-specific polygenic risk scores for blood pressure traits in a West African cohort

Introduction Genome-wide polygenic risk scores (PRSs) are useful for stratifying individuals' risk of polygenic diseases such as hypertension. However, a limitation of genome-wide PRSs is that they do not provide information about the distribution of risk burden across biological pathways. We used pathway-specific PRSs to investigate these effects of common antihypertensive therapy target pathways on disease risk in a cohort of West African individuals. Methods A total of 11 pathways, comprising 1,149 unique genes, were selected based on the targets of commonly used antihypertensive agents. Pathway-specific PRSs for hypertension [individuals with systolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥90 mmHg, or taking antihypertensive medications] were calculated in a cohort of 2,295 individuals. The model was then validated and tested in independent cohorts of 1,614 and 966 individuals, respectively. All participants were recruited from the International Collaborative Study on Hypertension in Blacks. Results In the combined pathway analysis, PRSs predicted risk better than base models fitted only with sex, age, and principal components. Compared with the base models without the PRSs, incremental increases in R 2 attributable to the inclusion of PRSs in predictive models were 2.6% for SBP ( p = 0.009), 1.4% for DBP ( p = 0.012), and 1.1% for mean arterial pressure (MAP) ( p = 0.044). PRSs from certain signaling pathways (mitogen-activated protein kinase, cAMP, and adrenergic signaling in cardiomyocytes) could stratify individuals into the top and bottom deciles of DBP risk. Adrenergic signaling in cardiomyocytes was also predictive of MAP when comparing individuals in the top and bottom deciles. Conclusions Combined pathway polygenic risk scores derived from genes in well-defined genetic pathways predict hypertension risk in individuals of African ancestry. However, the relatively low predictability of pathway-specific PRSs supports the need to explore the broader influence of genetic, environmental, and epigenetic factors that cannot be captured by pathway-specific PRSs alone.