The omnigenic model and polygenic prediction of complex traits

The omnigenic model was proposed as a framework to understand the highly polygenic architecture of complex traits revealed by genome-wide association studies (GWASs). I argue that this model also explains recent observations about cross-population genetic effects, specifically the low transferability of polygenic scores and the lack of clear evidence for polygenic selection. In particular, the omnigenic model explains why the effects of most GWAS variants vary between populations. This interpretation has several consequences for the evolutionary interpretation and practical use ofGWAS summary statistics and polygenic scores. First, some polygenic scores may be applicable only in populations of the same ancestry and environment as the discovery population. Second, most GWAS associations will have differing effects between populations and are unlikely to be robust clinical targets. Finally, it may not always be possible to detect polygenic selection from population genetic data. These considerations make it difficult to interpret the clinical and evolutionary meanings of polygenic scores without an explicit model of genetic architecture.

Automated summary

The omnigenic model explains the highly polygenic architecture of complex traits and the low transferability of polygenic scores between populations. Most GWAS variants show differing effects between populations, making it difficult to interpret their clinical and evolutionary implications without a clear model of genetic architecture.