Higher-order genetic interactions and their contribution to complex traits

The contribution of genetic interactions involving three or more loci to complex traits is poorly understood. These higher-order genetic interactions (HGIs) are difficult to detect in genetic mapping studies, therefore, few examples of them have been described. However, the lack of data on HGIs should not be misconstrued as proof that this class of genetic effect is unimportant. To the contrary, evidence from model organisms suggests that HGIs frequently influence genetic studies and contribute to many complex traits. Here, we review the growing literature on HGIs and discuss the future of research on this topic.