The Impact of Population Demography and Selection on the Genetic Architecture of Complex Traits

Abstract

Population genetic studies have found evidence for dramatic population growth in recent human history. It is unclear how this recent population growth, combined with the effects of negative natural selection, has affected patterns of deleterious variation, as well as the number, frequency, and effect sizes of mutations that contribute risk to complex traits. Because researchers are performing exome sequencing studies aimed at uncovering the role of low-frequency variants in the risk of complex traits, this topic is of critical importance. Here I use simulations under population genetic models where a proportion of the heritability of the trait is accounted for by mutations in a subset of the exome. I show that recent population growth increases the proportion of nonsynonymous variants segregating in the population, but does not affect the genetic load relative to a population that did not expand. Under a model where a mutation's effect on a trait is correlated with its effect on fitness, rare variants explain a greater portion of the additive genetic variance of the trait in a population that has recently expanded than in a population that did not recently expand. Further, when using a single-marker test, for a given false-positive rate and sample size, recent population growth decreases the expected number of significant associations with the trait relative to the number detected in a population that did not expand. However, in a model where there is no correlation between a mutation's effect on fitness and the effect on the trait, common variants account for much of the additive genetic variance, regardless of demography. Moreover, here demography does not affect the number of significant associations detected. These findings suggest recent population history may be an important factor influencing the power of association tests and in accounting for the missing heritability of certain complex traits.

Author Summary

Many human populations have dramatically expanded over the last several thousand years. I use population genetic models to investigate how recent population expansions affect patterns of mutations that reduce reproductive fitness and contribute to the genetic basis of complex traits (including common disease). I show that recent population growth increases the proportion of mutations found in the population that reduce fitness. When mutations that have the greatest effect on reproductive fitness also have the greatest effect on a complex trait, more of the heritability of the trait is due to mutations at very low-frequency in populations that have recently expanded, as compared to populations that have not. Also, under this model, for a given sample size and false-positive rate, fewer variants show statistically significant associations with the trait in the population that has expanded than in one that has not. Both of these findings suggest that recent population growth may make it more difficult to fully elucidate the genetic basis of complex traits that are directly or indirectly correlated with reproductive fitness.