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A model and test for coordinated polygenic epistasis in complex traits.

Brooke SheppardNadav RappoportPo-Ru LohStephan J SandersNoah A ZaitlenAndy Dahl
Published in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
  • genome wide
  • dna methylation
  • energy transfer
  • copy number
  • endothelial cells
  • high resolution
  • randomized controlled trial
  • gene expression
  • mass spectrometry