“Negative Selection on Complex Traits Limits Phenotype Prediction Accuracy between Populations”, 2021-03-09 (; similar):
Phenotype prediction is a key goal for medical genetics. Unfortunately, most genome-wide association studies are done in European populations, which reduces the accuracy of predictions via polygenic scores in non-European populations. Here, we use population genetic models to show that human demographic history and negative selection on complex traits can result in population-specific genetic architectures.
For traits where alleles with the largest effect on the trait are under the strongest negative selection, ~half of the heritability can be accounted for by variants in Europe that are absent from Africa, leading to poor performance in phenotype prediction across these populations. Further, under such a model, individuals in the tails of the genetic risk distribution may not be identified via polygenic scores generated in another population. We empirically test these predictions by building a model to stratify heritability between European-specific and shared variants and applied it to 37 traits and diseases in the UK Biobank. Across these phenotypes, ~30% of the heritability comes from European-specific variants.
We conclude that genetic association studies need to include more diverse populations to enable the utility of phenotype prediction in all populations.
[Keywords: negative selection, complex traits, polygenic scores, risk prediction, population history, population genetics, simulations]