A comprehensive genetic evaluation of molecular phenotypes in pigs: gaining knowledge through metabolite ratios

Metabolomics has emerged as a novel high-throughput approach for measuring all molecules at the basis of metabolism, providing an unprecedented picture of molecular phenotypes that contribute to describe the molecular phenome of an organism and define genetically determined metabolites. Within the molecular domain, molecules do not act in isolation but rather as part of networks. Specifically, two metabolites can be interconnected as substrates and products of an enzymatic reaction. Therefore, by exploiting this link, we can create new phenotypes (i.e. metabolite ratios) that expand the molecular phenome and provide novel insights into the molecular phenotype landscape. In this study, we obtained the metabolomic and genomic profile of ~700 Italian Large White pigs. Metabolite levels of 722 plasma metabolites were obtained using an untargeted metabolomic platform from Metabolon and genotypes were obtained with the Illumina 60k panel. Metabolite genome-wide association studies (mGWAS) were performed using the GEMMA tool. We then applied a powerful strategy that modelled metabolite relationships in the form of metabolite ratios, resulting in over more than 250,000 new molecular traits that underwent GWAS. The analysis of single metabolites identified several metabolite QTL (mQTL) regions involving 236 molecules and ~80 genes already known to be functionally linked to those metabolites, while metabolite ratios uncovered ~10 additional mQTL for additional 120 metabolites (and 450 ratios). Overall, by applying this powerful strategy, we expanded our knowledge of the molecular phenome, and its genetic control by ~300 times and uncovered new markers that can serve as proxies for more complex phenotypes. Acknowledgments: This study has received funding from the European Union’s Horizon Europe research and innovation programme under grant agreement No. 01059609 (Re-Livestock project).