Methodological Considerations When Using Polygenic Scores to Explore Parent-Offspring Genetic Nurturing Effects

BackgroundResearch has begun to explore the effects of parental genetic nurturing on offspring outcomes using polygenic scores (PGSs). However, there are concerns regarding potential biases due to confounding when mediating parental phenotypes are included. MethodsDepression, educational attainment and height PGSs were generated for 2680 biological parent-offspring trios using genome-wide association study (GWAS) meta-analysis summary statistics in a large population study: Generation Scotland. Regression and pathway models were estimated incorporating PGSs for both parents and offspring to explore direct (offspring PGS) and genetic nurturing (parental PGS) effects on psychological distress, educational attainment and height. Genetic nurturing via parental phenotypes were incorporated into the models. To explore sources of bias we conducted simulation analyses of 10,000 trios using combinations of PGS predictive accuracy and accounted variance. ResultsModels incorporating both offspring and parental PGSs suggested positive parental genetic nurturing effects on offspring educational attainment, but not psychological distress or height. In contrast, models additionally incorporating parental phenotypic information suggested positive parent phenotype mediated genetic nurturing effects were at play for all phenotypes explored as well as negative residual genetic nurturing effects for height. 10,000 parent-offspring trio effects (without genetic nurturing effects) were simulated. Simulations demonstrated that models incorporating parent and offspring PGSs resulted in genetic nurturing effects that were unbiased. However, adding parental phenotypes as mediating variables results in biased positive estimates of parent phenotype mediated genetic nurturing effects and negative estimates of residual genetic nurturing effects. Biased effects increased in magnitude as PGS accuracy and accounted variance decreased. These biases were only eliminated when PGSs were simulated to capture the entirety of trait genetic variance. ConclusionResults suggest that in the absence of PGSs that capture all genetic variance, parental phenotypes act as colliders in the same way as heritable environments. Relatively simple models combining parental and offspring PGSs can be used to detect genetic nurturing effects in complex traits. However, our findings suggest alternative methods should be utilised when aiming to identify mediating phenotypes and potentially modifiable parental nurturing effects.