Between candidate genes and whole genomes: time for alternative approaches in blood pressure genetics

Blood pressure has a significant genetic component, but less than 3% of the observed variance has been attributed to genetic variants identified to date. Candidate gene studies of rare, monogenic hypertensive syndromes have conclusively implicated several genes altering renal sodium balance, and studies of essential hypertension have inconsistently implicated over 50 genes in pathways affecting renal sodium balance and other functions. Genome-wide linkage scans have replicated numerous quantitative trait loci throughout the genome, and over 50 single nucleotide polymorphisms (SNPs) have been replicated in multiple genome-wide association studies. These studies provide considerable evidence that epistasis and other interactions play a role in the genetic architecture of blood pressure regulation, but candidate gene studies have limited scope to test for epistasis, and genome-wide studies have low power for both main effects and interactions. This review summarizes the genetic findings to date for blood pressure, and it proposes focused, pathway-based approaches involving epistasis, gene-environment interactions, and next-generation sequencing to further the genetic dissection of blood pressure and hypertension.