Omnigenic epistasis regulates complex trait heritability

The non-linear components of the genetic architecture of most common traits have been difficult to define. To better understand the architecture of complex traits we detected both main effect (additive) and epistatic QTLs in a sex-stratified manner in the Hybrid Mouse Diversity Panel. A high concordance of effects between males and females was observed for nearly all loci across the genome for both additive and epistatic effects, indicating that identified variants do not represent random noise. Instead, these results demonstrate that most loci contribute to trait heritability, consistent with an omnigenic model of inheritance that includes both additive and epistatic interactions. These findings demonstrate the role of genome-wide genetic interactions in the genetic architecture of complex mammalian traits and can explain why current genome-wide association studies fail to detect a considerable portion of trait heritability. ### Competing Interest Statement The authors have declared no competing interest.