A Narrative Review of the Genetic Architecture of Systemic Hypertension: From Candidate Genes to Biobank-Scale Genome-Wide Association Studies and Sequencing, With Translational Pathways to Precision Care

Systemic hypertension arises from the interplay of numerous common and rare genetic variants spanning vascular, renal, endocrine, metabolic, and immune pathways. Modern genomic approaches triangulate evidence from candidate gene studies, biobank-scale genome-wide association studies (GWAS), and whole-exome or whole-genome sequencing, enabling stronger mechanistic inference. In this narrative synthesis, we focused on recent human studies emphasizing candidate gene analyses, GWAS, and sequencing efforts in hypertension, extracting data on study design, populations, key variants, and implicated biological pathways. Across methodologies, genetic evidence consistently supported central roles for endothelial nitric-oxide biology (NOS3) and oxidative or tonic regulation of arteriolar resistance (PRKG1, CYBA, and CYP4A11), alongside contributions from lipid-handling genes (ApoB and PCSK9) and mitochondrial or smooth-muscle regulators (HSG and MFN2). GWAS conducted across diverse ancestries repeatedly mapped blood pressure variation to vascular calcium dynamics (ATP2B1 and CACN* loci), renal tubular transport mechanisms (UMOD and SLC4A7), renin-angiotensin-aldosterone system-related steroidogenesis (CYP17A1 and CYP11B2), and immune remodeling pathways (SH2B3), with several loci demonstrating sex- or ancestry-specific modulation and enrichment in resistant-hypertension cohorts, particularly within calcium-handling and steroidogenic pathways. Sequencing studies further identified rare, functional, and ancestry-specific variants, including large blood pressure-lowering alleles and signals enriched in Middle Eastern populations, that refine biological mechanisms and support population-tailored risk stratification. Overall, convergent evidence across genetic approaches highlights four translationally actionable systems, such as vascular calcium handling, renal salt and bicarbonate transport, adrenal steroidogenesis, and immune or inflammatory tone, supporting the development of ancestry-aware polygenic risk tools, genetic sub-phenotyping (including resistant hypertension), and mechanism-aligned therapeutics as key steps toward precision hypertension care.