Pathway-Specific Polygenic Risk Scores for Blood Pressure Traits in a West African Cohort

Area of Science:

• Genetics and Genomics
• Cardiovascular Disease Research
• Pharmacogenomics

Background:

• Genome-wide polygenic risk scores (PRS) aid in stratifying risk for polygenic diseases like hypertension.
• A limitation of genome-wide PRS is the lack of insight into risk distribution across biological pathways.
• Investigating pathway-specific PRS offers a more granular understanding of genetic contributions to disease risk.

Purpose of the Study:

• To assess the utility of pathway-specific polygenic risk scores (PRS) in predicting hypertension risk.
• To examine the predictive performance of PRS within anti-hypertensive therapy-target pathways.
• To analyze hypertension risk stratification in a West African cohort using pathway-specific PRS.

Main Methods:

• 11 biological pathways (1,149 genes) targeted by anti-hypertensive drugs were selected.
• Pathway-specific PRS were computed for hypertension in 2,395 individuals from the International Collaborative Study on Hypertension in Blacks.
• Models were validated and tested in separate cohorts of 1,614 and 966 individuals, respectively.

Main Results:

• Combined pathway PRS improved hypertension risk prediction beyond traditional models (sex, age, principal components).
• Inclusion of PRS incrementally increased R-squared for systolic blood pressure (2.6%), diastolic blood pressure (1.4%), and mean arterial pressure (1.1%).
• Specific pathways (MAPK, cAMP, adrenergic signaling) demonstrated ability to stratify individuals by diastolic blood pressure and mean arterial pressure.

Conclusions:

• Pathway-specific polygenic risk scores derived from well-defined genetic pathways can predict hypertension risk in individuals of African ancestry.
• The relatively low predictability of pathway-specific PRS underscores the importance of integrating broader genetic, environmental, and epigenetic factors.
• Further research is needed to capture the full spectrum of factors influencing hypertension risk beyond pathway-specific genetic contributions.