Key result
Combined pathway polygenic risk scores improve SBP prediction by ~3% in a West African cohort.
Why the study?
Genome-wide polygenic risk scores lack information regarding how risk burden is distributed across biological pathways.
Does a pathway-specific polygenic risk score improve the prediction of blood pressure traits and hypertension risk in individuals of West African ancestry?
Cohort (n=4,975)
Yes
Does a pathway-specific polygenic risk score improve the prediction of blood pressure traits and hypertension risk in individuals of West African ancestry?
Effect estimate: R2 increment 2.6%
p-value: p=0.009
Pathway-specific polygenic risk scores based on anti-hypertensive medication targets provide a modest but significant improvement in predicting blood pressure traits in individuals of West African ancestry.
May modestly improve SBP prediction in West African ancestry; leaves open clinical utility for hypertension risk stratification.
Introduction: Genome-wide polygenic risk scores (PRS) are useful for stratifying individuals' risk for polygenic diseases such as hypertension. However, a downside of genome-wide PRS is the lack of information about the distribution of risk burden across biologic pathways. We used pathway-specific PRS to investigate these effects within common anti-hypertensive therapy-target pathways on disease risk in a cohort of West Africans. Methods: A total of 11 pathways comprising 1,149 unique genes were selected based on the targets of common anti-hypertensive agents. Pathway-specific PRS for hypertension (individuals with systolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥90 mmHg, or taking anti-hypertensive medications) were computed in a cohort of 2,395 individuals. The model was then validated and tested in 1,614 and 966 separate individuals, respectively. All participants were recruited from the International Collaborative Study on Hypertension in Blacks. Results: attributable to inclusion of PRS 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.) PRS from certain pathways (MAPK, cAMP, and adrenergic signaling in cardiomyocytes) could stratify individuals in the top and bottom deciles for DBP. Adrenergic signaling in cardiomyocytes was also predictive of MAP when comparing top and bottom deciles. Conclusions: Combined pathway polygenic risk scores constructed from genes in well-defined genetic pathways predict hypertension risk in individuals of African ancestry. However, pathway-specific PRS's relatively low predictability supports the need to explore the broader influence of genetic, environmental, and epigenetic factors that cannot be captured by pathway-specific PRS alone.
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Bormes et al. (2025) conducted a cohort in Hypertension (n=4,975). Combined pathway polygenic risk scores (PRS) vs. Base models (sex, age, and principal components only) was evaluated on Incremental increase in R2 for systolic blood pressure (SBP) (R2 increment 2.6%, p=0.009). Combined pathway polygenic risk scores significantly improved the prediction of systolic blood pressure, increasing the model's R2 by 2.6% (p=0.009) compared to base models in a West African cohort.
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