Advances in molecular genetics have provided well-defined physical genetic maps and large numbers of genetic markers for both model organisms and humans. It is now possible to gain a fundamental understanding of the genetic architecture underlying quantitative traits, of which blood pressure (BP) is an important example. This review emphasizes analytical techniques and results obtained using the Dahl salt-sensitive (S) rat as a model of hypertension by presenting results in detail for three specific chromosomal regions harboring genetic elements of increasing complexity controlling BP. These results highlight the critical importance of genetic interactions (epistasis) on BP at all levels of structure, intragenic, intergenic, intrachromosomal, interchromosomal, and across whole genomes. In two of the three examples presented, specific DNA structural variations leading to biochemical, physiological, and pathological mechanisms are well defined. This proves the usefulness of the techniques involving interval mapping followed by substitution mapping using congenic strains. These classic techniques are compared to newer approaches using sophisticated statistical analysis on various segregating or outbred model-organism populations, which in some cases are uniquely useful in demonstrating the existence of higher-order interactions. It is speculated that hypertension as an outlier quantitative phenotype is dependent on higher-order genetic interactions. The obstacle to the identification of genetic elements and the biochemical/physiological mechanisms involved in higher-order interactions is not theoretical or technical but the lack of future resources to finish the job of identifying the individual genetic elements underlying the quantitative trait loci for BP and ascertaining their molecular functions. © 2019 American Physiological Society. Compr Physiol 9:1305-1337, 2019.
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