A model and test for coordinated polygenic epistasis in complex traits

Brooke Sheppard, Nadav Rappoport, Po Ru Loh, Stephan J. Sanders, Noah Zaitlen, Andy Dahl

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish
Article numbere1922305118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number15
StatePublished - 13 Apr 2021
Externally publishedYes


  • Epistasis
  • Genetics
  • Polygenic risk

ASJC Scopus subject areas

  • General


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