Molecular Systems, Human Noncoding Sequence Variants, and Blood Pressure

The human genome harbors millions of noncoding sequence variants. Genome-wide association studies (GWAS) have identified thousands of robust associations linking noncoding variants to human physiological traits and complex diseases. Integrative approaches, including expression quantitative trait locus mapping, epigenomic profiling, and precise genome editing in trait-relevant cell types, enable the identification of effector genes and underlying regulatory mechanisms, such as long-range chromatin interactions, that mediate the effects of noncoding variants. Investigations of blood pressure (BP)-associated noncoding sequence variants have uncovered previously unrecognized roles of genes in BP regulation, reinforced the human genetic relevance of established BP regulatory pathways, and elucidated specific regulatory mechanisms by which noncoding variants influence gene expression and BP. Studies of orthologous noncoding genomic regions in animal models corresponding to human genomic regions harboring BP-associated variants have demonstrated substantial effects on BP, suggesting that the phenotypic impact of noncoding sequence variants may be large within human subgroups. Continued expansion of functional studies of trait-associated noncoding sequence variants, together with advances in mapping molecular quantitative trait loci and epigenomic landscapes, will provide novel insights directly relevant to human biology and disease and essential for understanding humans as molecular systems.