Effect of Genotype Imputation on Genome-Enabled Prediction of Complex Traits: an Empirical Study With Mice Data

Abstract

Background: Genotype imputation is an important tool for whole-genome prediction as it allows cost reduction of individual genotyping. However, benefits of genotype imputation have been evaluated mostly for linear additive genetic models. In this study we investigated the impact of employing imputed genotypes when using more elaborated models of phenotype prediction. Our hypothesis was that such models would be able to track genetic signals using the observed genotypes only, with no additional information to be gained from imputed genotypes. Results: For the present study, an outbred mice population containing 1,904 individuals and genotypes for 1,809 pre-selected markers was used. The effect of imputation was evaluated for a linear model (the Bayesian LASSO-BL) and for semi and non-parametric models (Reproducing Kernel Hilbert spaces regressions-RKHS, and Bayesian Regularized Artificial Neural Networks-BRANN, respectively). The RKHS method had the best predictive accuracy. Genotype imputation had a similar impact on the effectiveness of BL and RKHS. BRANN predictions were, apparently, more sensitive to imputation errors. In scenarios where the masking rates were 75% and 50%, the genotype imputation was not beneficial. However, genotype imputation incorporated information about important markers and improved predictive ability, especially for body mass index (BMI), when genotype information was sparse (90% masking), and for body weight (BW) when the reference sample for imputation was weakly related to the target population. Conclusions: In conclusion, genotype imputation is not always helpful for phenotype prediction, and so it should be considered in a case-by-case basis. In summary, factors that can affect the usefulness of genotype imputation for prediction of yet-to-be observed traits are: the imputation accuracy itself, the structure of the population, the genetic architecture of the target trait and also the model used for phenotype prediction.