a covariate if the polygenic score for alcohol consumption is correlated with educational attainment. Previous work demonstrates that alcohol consumption is genetically correlated with educational attainment (Sanchez-Roige et al., 2019; Walters et al., 2018; Zhou et al., 2020). Furthermore, educational attainment has been shown to be correlated with a wide variety of other unmeasured variables, such as personality (Mõttus et al., 2017), internalizing behavior, and externalizing behavior (Veldman et al., 2014). There are many possible mechanisms that give rise to the correlations between a polygenic score, the target phenotype from its corresponding discovery GWAS, a heritable environment that might be used as a covariate, and the wide variety of unmeasured variables that can be correlated with the target phenotype and environment. Regardless, they share a common consequence in polygenic association studies: biasing PRS effect size estimation. The partial effect size of the PRS (β) and the variance accounted for by the PRS (R2) are reduced, while the estimate of the variance accounted for by the PRS and environment together is inflated (Akimova et al., 2021). If the effect of unmeasured confounding variables can be approximated and accounted for, bias in polygenic associations may be reduced.
