Variant effects depend on polygenic background: experimental, clinical, and evolutionary implications

Both rare and common genetic variants contribute to human disease, and emerging evidence suggests that they combine additively to influence disease liability. However, due to the non-linear relationship between disease liability and disease prevalence, risk variants have more severe phenotypic consequences in high-risk polygenic backgrounds. Consequently, selecting individuals with appropriate polygenic backgrounds may improve variant characterization experiments, as disease-relevant phenotypes may be masked or revealed in different genomic contexts. Simultaneously, selection has limited power to eliminate risk variants because they have minimal impact in low polygenic risk backgrounds, yet is more powerful with higher polygenicity because more individuals achieve genetic and phenotypic extremes. This dependence on polygenic background means that selection acting on an allele should be modeled as a distribution that differs across populations, time, environments, and individuals rather than as a single value. Overall, considering polygenic backgrounds will be critical when investigating the origins of complex traits.