Genetic architecture of the murine serum metabolome reveals carboxyl esterases as master regulators of circulating fatty acid metabolism

BACKGROUND: The systemic biochemical diversity of circulating metabolites and lipids reflects the integrated effects of genetic variation and environmental exposure. Metabolite quantitative trait locus (mQTL) studies in humans have established gene-metabolite associations, but genetic contributions can be obscured by sex, diet, age, medication use, and environmental exposures. Genetically diverse model systems offer a powerful complementary strategy to isolate genetic contributions to the biochemical diversity of the circulating metabolome. METHODOLOGY/PRINCIPAL FINDINGS: We applied mass spectrometry profiling to serum samples in 541 mice from the Diversity Outbred (DO) population and identified 1,933 mQTL across 240 metabolites, 561 lipids, 43 oxylipins, and 4,465 MS/MS features. QTL hotspots on chromosomes 8, 9, 10, and 17 implicated distinct loci in the regulation of serum lipids, metabolites, and peptide-like features. The chromosome 8 Ces1 and Ces2 gene clusters were associated with lipids, acylcarnitines, and acyl-CoAs, while chromosome 9 and 10 loci included additional lipid and metabolite QTL. On chromosome 17, MHC and C3 regions were associated with untargeted peptide-like MS/MS features. Comparisons with matched red blood cell mQTL revealed widespread compartment-specific genetic control. CONCLUSIONS/SIGNIFICANCE: Collectively, these findings provide a high-resolution map of the genetic regulation of the circulating metabolome, offering mechanistic insights that complement and extend human metabolic genetics.