Genomics of Blood Pressure and Hypertension: Extending the Mosaic Theory Toward Stratification

Abstract

The genetic architecture of blood pressure (BP) now includes more than 30 genes, with rare mutations resulting in inherited forms of hypertension or hypotension, and 1477 common single-nucleotide polymorphisms (SNPs). These signify the heterogeneity of the BP phenotype and support the mosaic theory of hypertension. The majority of monogenic syndromes involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, and a smaller fraction are due to rare neuroendocrine tumours of the adrenal glands and the sympathetic and parasympathetic paraganglia. Somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and adenosine triphosphatases (ATP1A1 and ATP2B3) highlight the central role of calcium signalling in autonomous aldosterone production by the adrenal gland. The per-SNP BP effect is small for SNPs according to genome-wide association studies (GWAS), and all of the GWAS-identified BP SNPs explain ∼ 27% of the 30%-50% estimated heritability of BP. Uromodulin is a novel pathway identified by GWAS, and it has now progressed to a genotype-directed clinical trial. The majority of the GWAS-identified BP SNPs show pleiotropic associations, and unravelling those signals and underpinning biological pathways offers potential opportunities for drug repurposing. The GWAS signals are predominantly from Europe-centric studies with other ancestries underrepresented, however, limiting the generalisability of the findings. In this review, we leverage the burgeoning list of polygenic and monogenic variants associated with BP regulation along with phenome-wide studies in the context of the mosaic theory of hypertension, and we explore potential translational aspects that underlie different hypertension subtypes.

Figure 1

Pathways in the circulatory, endocrine, and neurologic systems that are associated with monogenic forms of hypertension. Causal monogenic genes and their syndromes are described in Table 1.

Figure 2

Word cloud generated from all of the genome-wide association studies–identified blood pressure (BP) single-nucleotide polymorphism (SNP) associations with non-BP traits with a P value threshold of 58 × 10⁻⁵. The size of the words indicates the weight based on the number of independent BP SNPs associated with each phenotype.

Figure 3

Pharmacogenetic landscape of blood pressure. The Circos plot shows all the genome-wide association studies–identified blood pressure single-nucleotide polymorphisms (SNPs) and their putatively linked genes that show interaction with licensed antihypertensive drugs. Monogenic genes are presented in red and GWAS SNP genes in dark grey. Chromosomes are represented as numbered bands. The coloured square and circular markers indicate the number of antihypertensive drug classes that each gene interacts with. Drug-gene interactions were obtained from the DrugBank and Comparative Toxicogenomics Database.