Coordinated Interaction: A model and test for globally signed epistasis in complex traits

Interactions between genetic variants – epistasis – is pervasive in model systems and can profoundly impact evolutionary adaption, population disease dynamics, genetic mapping, and precision medicine efforts. In this work we develop a model for structured polygenic epistasis, called (CI), and prove that several recent theories of genetic architecture fall under the formal umbrella of CI. Unlike standard polygenic epistasis models that assume interaction and main effects are independent, in the CI model, sets of SNPs broadly interact positively or negatively, on balance skewing the penetrance of main genetic effects. To test for the existence of CI we propose the (EO) test and prove it is calibrated in a range of realistic biological models. Applying the EO test in the UK Biobank, we find evidence of CI in 14 of 26 traits spanning disease, anthropometric, and blood categories. Finally, we extend the EO test to tissue-specific enrichment and identify several plausible tissue-trait pairs. Overall, CI is a new dimension of genetic architecture that can capture structured, systemic interactions in complex human traits.