Polygenic backgrounds influence phenotypic consequences of variants in cells, individuals, and populations

Abstract Both rare and common genetic variants contribute to human disease, and emerging evidence suggests that they combine additively to influence disease liability. However, the non-linear relationship between disease liability and disease prevalence means that risk variants may have more severe phenotypic consequences in high-risk polygenic backgrounds and minimal impact in low-risk backgrounds, resulting in uneven selection across the population. As a result, selection coefficients may be better modeled as distributions that differ across populations, time, environments, and individuals rather than single values. Further, the number of genes contributing to a trait and epistasis between alleles enhance negative selection due to the increased variance pushing more individuals to phenotypic extremes. Because disease-relevant phenotypes may be masked in certain genetic backgrounds, polygenic background should be considered when characterizing the molecular underpinnings of complex traits. Competing Interest Statement The authors have declared no competing interest. Footnotes Substantial modifications have been made throughout the manuscript to improve the presentation of our results and better contextualize them within the current context of the field. Sections of the manuscript have been rearranged so that it concludes with the most forward-looking content. Additional detail has been added to the text to better explain the disease liability simulations, and new data for disease liability with an epistatic interaction model has been added. Additional references have been added to better support assumptions about variant effect additivity in different disease contexts and how disease liability interacts with selection.