A model and test for coordinated polygenic 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 coordinated epistasis (CE), and prove that several recent theories of genetic architecture fall under the formal umbrella of CE. Unlike standard epistasis models that assume epistasis and main effects are independent, CE captures systematic correlations between epistasis and main effects that result from pathway-level epistasis, on balance skewing the penetrance of genetic effects. To test for the existence of CE, we propose the even-odd (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 CE in 18 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, CE is a dimension of genetic architecture that can capture structured, systemic forms of epistasis in complex human traits.

The code to generate internal and external PRS, to perform EO CE and tissue-specific tests, and to reproduce simulations can be found at https://github.com/nadavrap/CoordinatedInteractions. R Markdown notebook to interactively explore CE and the EO test in a range of simulation settings can be found at https://github.com/nadavrap/CoordinatedInteractions/tree/master/simulations. UKBB data are available through the UK Biobank Access Management System. Detailed instructions can be found at https://www.ukbiobank.ac.uk/register-apply/.