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

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 than as single values. As the number of genes contributing to a trait and epistasis between alleles increases, so does phenotypic variance, pushing more individuals to extreme phenotypes and enhancing negative selection. Because disease-relevant phenotypes may be masked in certain genetic backgrounds, we argue that the polygenic background should be considered when designing experiments to characterize the molecular underpinnings of complex traits.