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

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.

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.

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.

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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by NIH grants from the National Human Genome Research Institute (1U01HG011717) and the National Heart, Lung and Blood Institute (HL053353). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB of Loyola University Chicago Health Sciences Division waived ethical approval for this project. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors.