When we are interested in dissecting the genotype-phenotype map for complex traits and common disease, knowledge about epistatic gene action is important. To understand why, consider the case of epistasis illustrated above. If alleles A 2 and B 2 are rare, there will be very few diseased individuals in the population and the individual effects of locus A and locus B on disease risk will be very small. In this case, most of the genetic variance will be additive, and the additive effects of these loci will have a negligible impact on the ability to predict the risk of the disease. If there were many other loci for which a similar situation applied, this could generate the appearance of a highly polygenic genetic architecture for the disease, with many segregating alleles with very small effects. This is indeed what has been observed for most complex human diseases and quantitative traits. This phenomenon has been called ‘missing heritability’, because the mapped variants have small effects and together only account for a small fraction of the total genetic variance known to affect the traits. In this scenario, additivity is an emergent property of underlying epistatic interaction networks. Epistasis could thus partially explain the missing heritability. However, knowing the genotypic status of both loci is critical if one happens to be A 2 A 2 B 2 B 2 , and predictive ability when both loci are accounted for would be excellent. In genomic medicine, one does not wish to know the population average effect of a variant at a locus, but rather the effect of one’s particular genotype.

Epistatic gene action will also yield different genetic architectures between populations in which the frequency of the causal alleles vary. For example, consider the same example of epistasis discussed above, but in a population where the frequencies of the A 2 and B 2 alleles are high. Such a population would have a high prevalence of disease, and the average effects of both the A and B loci would be appreciable. This would manifest as an unreplicated association in the population in which the A 2 and B 2 alleles are rare, yet gene action is identical in the two populations. Thus, the typical requirement that genotype-phenotype associations in humans be replicated across populations will not be met in the presence of epistasis when allele frequencies vary among populations [6].