Opportunities and limits of combining microbiome and genome data for complex trait prediction.

Background: Analysis and prediction of complex traits using microbiome data combined with host genomic information is a topic of utmost interest. However, numerous questions remain to be answered: how useful can the microbiome be for complex trait prediction? Are estimates of microbiability reliable? Can the underlying biological links between the host's genome, microbiome, and phenome be recovered?

Methods: Here, we address these issues by (i) developing a novel simulation strategy that uses real microbiome and genotype data as inputs, and (ii) using variance-component approaches (Bayesian Reproducing Kernel Hilbert Space (RKHS) and Bayesian variable selection methods (Bayes C)) to quantify the proportion of phenotypic variance explained by the genome and the microbiome. The proposed simulation approach can mimic genetic links between the microbiome and genotype data by a permutation procedure that retains the distributional properties of the data.

Results: Using real genotype and rumen microbiota abundances from dairy cattle, simulation results suggest that microbiome data can significantly improve the accuracy of phenotype predictions, regardless of whether some microbiota abundances are under direct genetic control by the host or not. This improvement depends logically on the microbiome being stable over time. Overall, random-effects linear methods appear robust for variance components estimation, in spite of the typically highly leptokurtic distribution of microbiota abundances. The predictive performance of Bayes C was higher but more sensitive to the number of causative effects than RKHS. Accuracy with Bayes C depended, in part, on the number of microorganisms' taxa that influence the phenotype.

Conclusions: While we conclude that, overall, genome-microbiome-links can be characterized using variance component estimates, we are less optimistic about the possibility of identifying the causative host genetic effects that affect microbiota abundances, which would require much larger sample sizes than are typically available for genome-microbiome-phenome studies. The R code to replicate the analyses is in https://github.com/miguelperezenciso/simubiome .