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

doi:10.1073/pnas.1922305118

A model and test for coordinated polygenic epistasis in complex traits

Proc Natl Acad Sci U S A. 2021 Apr 13;118(15):e1922305118. doi: 10.1073/pnas.1922305118.

Authors

Brooke Sheppard¹, Nadav Rappoport^{1

2}, Po-Ru Loh^{3

4}, Stephan J Sanders¹, Noah Zaitlen^{5

6

7}, Andy Dahl^{8

7

9}

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143.
² Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA 94143.
³ Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142.
⁴ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
⁵ Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143; nzaitlen@ucla.edu andywdahl@uchicago.edu.
⁶ Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095.
⁷ Department of Computational Medicine, University of California Los Angeles, Los Angeles, CA 90095.
⁸ Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095; nzaitlen@ucla.edu andywdahl@uchicago.edu.
⁹ Section of Genetic Medicine, University of Chicago, Chicago, IL 60637.

Abstract

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.

Keywords: epistasis; genetics; polygenic risk.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Epistasis, Genetic*
Evolution, Molecular
Genetic Predisposition to Disease
Humans
Models, Genetic*
Multifactorial Inheritance / genetics*
Quantitative Trait, Heritable

Abstract

Publication types

MeSH terms

Grants and funding