Blood Pressure Genome-Wide Association Studies, Missing Heritability, and Omnigenics.

The past 4 decades have seen enormous progress toward understanding the genetic basis of complex polygenic traits. In the hypertension field, the search began with a simple association study of a restriction fragment length polymorphism in the human renin gene in 1988.1 Although the result was negative, it was followed by a plethora of studies comparing allele frequencies of polymorphisms in potential candidate genes in subjects with essential hypertension with allele frequencies in subjects with normal blood pressure. There were also linkage studies involving pedigrees affected by rare monogenic forms of hypertension. Soon, positive results began to emerge for essential hypertension2,3 and in identification of single gene mutations responsible for various forms of familial hypertension.4 In addition, linkage analyses were used to identify hypertension loci in rat models of hypertension5 and in essential hypertension. Positive findings from the human studies emerged from sib-pair analysis of restriction fragment length polymorphisms at the angiotensinogen gene locus on chromosome 1,3 in a sib-pair study of microsatellite markers spanning all of chromosome 1,6 and by genome-wide linkage analysis.7–9 Next came large-scale genome-wide association studies (GWAS) involving single nucleotide polymorphisms (SNPs) aimed at identification of all genetic loci for blood pressure and essential hypertension.10 These became, and remain, the tour de force for studies of complex polygenic diseases. More recently, transcriptome-wide studies have been undertaken.11 These identify, but do not discriminate between, genes that are either directly or indirectly involved in hypertension. The first human study, my my Lab, resulted in the comprehensive identification of numerous messenger RNAs and microRNAs differentially expressed in the kidney in essential hypertension.11 The study further identified a potential causative mechanism whereby microRNA-mediated repression of the renin gene is lost in hypertensives, so increasing renal renin …