ORIGINAL RESEARCH article
Front. Cardiovasc. Med.
Sec. Cardiovascular Genetics and Systems Medicine
Pathway-Specific Polygenic Risk Scores for Blood Pressure Traits in a West African Cohort
Gregory Bormes 1
Vanessa Robbin 1
Tinashe Chikwore 2,3
Yuji Zhang 4
Ananyo Choudhury 5
Scott Hazelhurst 5,6
Neil Hanchard 7
Sally N Adebamowo 4,8
Adebowale Adeyemo 9
Bamidele Tayo 10
1. Loyola University Chicago Stritch School of Medicine, Maywood, United States
2. Harvard Medical School, Boston, United States
3. Brigham and Women's Hospital Channing Division of Network Medicine, Boston, United States
4. University of Maryland Baltimore Department of Epidemiology & Public Health, Baltimore, United States
5. University of the Witwatersrand Johannesburg Sydney Brenner Institute for Molecular Bioscience, Johannesburg, South Africa
6. University of the Witwatersrand Johannesburg School of Electrical and Information Engineering, Johannesburg, South Africa
7. National Human Genome Research Institute Center for Precision Health Research, Bethesda, MD, United States
8. University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States
9. National Human Genome Research Institute Center for Research on Genomics and Global Health, Bethesda, United States
10. Department of Public Health Sciences, Loyola University Parkinson School of Health Sciences and Public Health, Maywood, IL, United States
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Abstract
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 2,295 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: In combined pathways analysis, PRS predicted risk better than base models fitted with only sex, age, and principal components. Compared to base models without the PRS, the incremental increases in R2 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.
Summary
Keywords
Anti-hypertensive agents, Blood Pressure Traits, Genome wide association study (GWAS), Pathway-specific, polygenic risk scores
Received
17 September 2025
Accepted
18 February 2026
Copyright
© 2026 Bormes, Robbin, Chikwore, Zhang, Choudhury, Hazelhurst, Hanchard, Adebamowo, Adeyemo and Tayo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Bamidele Tayo
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