Maintenance of Complex Trait Variation: Classic Theory and Modern Data

Numerous studies have found evidence that GWAS loci experience negative selection, which increases in intensity with the effect size of identified variants. However, there is also accumulating evidence that this selection is not entirely mediated by the focal trait and contains a substantial pleiotropic component. Understanding how selective constraint shapes phenotypic variation requires advancing models capable of balancing these and other components of selection, as well as empirical analyses capable of inferring this balance and how it is generated by the underlying biology. We first review the classic theory connecting phenotypic selection to selection at individual loci as well as approaches and findings from recent analyses of negative selection in GWAS data. We then discuss geometric theories of pleiotropic selection with the potential to guide future modeling efforts. Recent findings revealing the nature of pleiotropic genetic variation provide clues to which genetic relationships are important and should be incorporated into analyses of selection, while findings that effect sizes vary between populations indicate that GWAS measurements could be misleading if effect sizes have also changed throughout human history.

Automated summary

Numerous studies have found evidence of negative selection at GWAS loci, which is correlated with the effect size of identified variants but is not entirely mediated by the focal trait, also involving a pleiotropic component. Balancing models and empirical analyses are needed to understand how selective constraint shapes phenotypic variation, with recent findings shedding light on the importance of genetic relationships and the potential for GWAS measurements to be misleading due to changing effect sizes throughout human history.