Genetic reference panels (GRPs) using model organisms have become a more tractable way of studying the influence of genetics and environment on complex metabolic traits. Unlike studies in humans, GRPs allow for accurate control of environment as well as access to critical metabolic tissues. Importantly, systems genetic integration with intermediate phenotypes such as proteomic and lipidomic analysis of such tissues facilitates the discovery of previously unknown linkages between several layers of molecular information. Here, we present our latest systems genetic analysis of the Hybrid Mouse Diversity Panel involving the integration of genomics with proteomics and lipidomics analysis in liver from >100 strains of mice. This revealed functional protein and genetic variants that modulate pathological lipid abundance including the validation of PSMD9 as a previously unknown lipid regulatory protein. To further understand how genetic variants influence potential adaptations to the environment, we have also integrated the quantification of lysine acetylation modifications across >70 strains of mice. A trans-quantitative trait loci analysis has identified precise SNPs that are associated with modification sites. Integration of these data with established mouse GWAS has revealed novel causative mutations effecting histone modifications and whole-body metabolic traits. Associating natural variations in the abundance of PTMs across a GRP to phenotypic measurements is a powerful approach to pinpoint functional modifications influencing gene expression and metabolism.