Multiomic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

We profiled the liver transcriptome, proteome, and metabolome from 347 individuals from 58 isogenic strains of the BXD mouse population across age (7 to 24 months) and diet (low or high fat) to link molecular variations to metabolic traits. Several hundred genes are affected by diet and/or age at the transcript and protein levels. Orthologs of two aging-associated genes, St7 and Ctsd, were knocked down in C. elegans, reducing longevity in wildtype and mutant long-lived strains. The multiomics data were analyzed as segregating gene networks according to each independent variable, providing causal insight into segregating edges. Candidate hits were cross-examined in an independent Diversity Outbred mouse liver dataset segregating for similar diets, with ~80-90% of diet-related candidate genes found in common across datasets. Together, we have developed a large multiomics resource for multivariate analysis of complex traits and demonstrate a methodology for moving from observational associations to causal connections.