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Significance Systems-level interactions across physiological pathways, cell types, and tissues are core biological elements widely studied across diverse fields including evolution, systems biology, and model-organism genetics. However, they are essentially ignored in human genetics, and existing approaches fail to interpretably explain substantial complex trait heritability. Here, we propose the coordinated epistasis model of complex phenotypes that generalizes several recently proposed theoretical epistatic architectures of human traits. Broadly, coordination measures the degree to which epistasis effects act in concert with respect to marginal effects. It summarizes a dimension of polygenic effects orthogonal to parameters like heritability and standard estimates of epistasis.

A model and test for coordinated polygenic epistasis in complex traits