Merging metabolomics and genomics provides a catalog of genetic factors that influence molecular phenotypes in pigs linking relevant metabolic pathways

Background. Metabolomics opens novel avenues to study the basic biological mechanisms underlying complex traits, starting from characterization of metabolites. Metabolites and their levels in a biofluid represent simple molecular phenotypes (metabotypes) that are direct products of enzyme activities and relate to all metabolic pathways, including catabolism and anabolism of nutrients. In this study, we demonstrated the utility of merging metabolomics and genomics in pigs to uncover a large list of genetic factors that influence mammalian metabolism. Results. We obtained targeted characterization of the plasma metabolome of more than 1300 pigs from two populations of Large White and Duroc pig breeds. The metabolomic profiles of these pigs were used to identify genetically influenced metabolites by estimating the heritability of the level of 188 metabolites. Then, combining breed-specific genome-wide association studies of single metabolites and their ratios and across breed meta-analyses, we identified a total of 97 metabolite quantitative trait loci (mQTL), associated with 126 metabolites. Using these results, we constructed a human-pig comparative catalog of genetic factors influencing the metabolomic profile. Whole genome resequencing data identified several putative causative mutations for these mQTL. Additionally, based on a major mQTL for kynurenine level, we designed a nutrigenetic study feeding piglets that carried different genotypes at the candidate gene kynurenine 3-monooxygenase (KMO) varying levels of tryptophan and demonstrated the effect of this genetic factor on the kynurenine pathway. Furthermore, we used metabolomic profiles of Large White and Duroc pigs to reconstruct metabolic pathways using Gaussian Graphical Models, which included perturbation of the identified mQTL. Conclusions. This study has provided the first catalog of genetic factors affecting molecular phenotypes that describe the pig blood metabolome, with links to important metabolic pathways, opening novel avenues to merge genetics and nutrition in this livestock species. The obtained results are relevant for basic and applied biology and to evaluate the pig as a biomedical model. Genetically influenced metabolites can be further exploited in nutrigenetic approaches in pigs. The described molecular phenotypes can be useful to dissect complex traits and design novel feeding, breeding and selection programs in pigs.