{ "abstract": "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. Author summary: The levels of metabolites and lipids circulating in blood are influenced by both genetics and exposures, including the diet and environment, making it difficult to determine how inherited variation shapes metabolism in humans. Here, we used genetically diverse Diversity Outbred mice to examine the genetic regulation of the serum metabolome under controlled experimental conditions. Using mass spectrometry, we profiled metabolites, lipids, oxylipins, and thousands of additional molecular features in 541 mice and mapped 1,933 genetic associations. Several genomic regions emerged as major regulators of circulating metabolism. In particular, carboxylesterase (Ces) gene clusters on chromosome 8 were strongly associated with variation in lipids, acylcarnitines, and acyl-CoAs, while additional loci on chromosomes 9 and 10 influenced distinct lipid and metabolite pathways. We also identified genetic associations with peptide-like features at regions containing immune-related genes, including the major histocompatibility complex and complement C3. Comparison with matched red blood cell data showed that most genetic effects were specific to the biological compartment examined. Together, these findings provide a detailed reference map linking genetic variation to circulating biochemical diversity and highlight candidate pathways for future studies of metabolic regulation and disease.", "abstract_shown": true, "affiliations": [ "RTI International, Research Triangle Park, North Carolina, United States of America", "The Jackson Laboratory, Bar Harbor, Maine, United States of America", "Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, Colorado, United States of America", "Omix Technologies Inc, Aurora, Colorado, United States of America", "Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America", "Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada", "Canadian Blood Services, Ottawa, Ontario, Canada" ], "article_type": "Research Article", "arxiv": null, "author_total": 10, "authors": [ { "affs": [ 0 ], "name": "Gregory R. Keele" }, { "affs": [ 1 ], "name": "Travis Nemkov" }, { "affs": [ 2 ], "name": "Ariel M. Hay" }, { "affs": [ 3 ], "name": "Matthew Vincent" }, { "affs": [ 4 ], "name": "Callan O'Connor" }, { "affs": [ 5 ], "name": "Daniel Stephenson" }, { "affs": [ 6 ], "name": "Grier P. Page" }, { "name": "James C. Zimring" }, { "name": "Gary A. Churchill" }, { "name": "Angelo D’Alessandro" } ], "bibtex": "https://research.draconitic.com/paper/8drvyh2zmtr58.bib", "cited_by": 0, "doi": "10.1371/journal.pgen.1012223", "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012223", "id": "8drvyh2zmtr58", "issns": [ "1553-7404" ], "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012223", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1312|Metabolomics and Mass Spectrometry Studies" ], [ "plos", "/Biology and life sciences/Biochemistry/Lipids" ], [ "plos", "/Biology and life sciences/Biochemistry/Lipids/Lipid metabolism" ], [ "plos", "/Biology and life sciences/Biochemistry/Metabolism/Lipid metabolism" ], [ "plos", "/Biology and life sciences/Biochemistry/Metabolism/Metabolites" ], [ "plos", "/Biology and life sciences/Evolutionary biology/Population genetics/Genetic polymorphism" ], [ "plos", "/Biology and life sciences/Genetics/Genetic loci" ], [ "plos", "/Biology and life sciences/Genetics/Genetic loci/Quantitative trait loci" ], [ "plos", "/Biology and life sciences/Genetics/Heredity/Genetic mapping/Haplotypes" ], [ "plos", "/Biology and life sciences/Genetics/Population genetics/Genetic polymorphism" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Gene mapping" ], [ "plos", "/Biology and life sciences/Population biology/Population genetics/Genetic polymorphism" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Gene mapping" ] ], "openalex": "W7166555499", "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012223&type=printable", "pmcid": null, "pmid": null, "published": "2026-11-02", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/8drvyh2zmtr58.ris", "sources": [ { "first_seen": "2026-11-03T12:20:16Z", "native_id": "10.1371/journal.pgen.1012223", "source": "plos", "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012223" } ], "subjects": [ { "field": "biochemistry", "origin": "plos:metabolism", "subfield": "enzymology-metabolism" }, { "field": "biology", "origin": "plos:genetics", "subfield": "genetics-genomics" } ], "title": "Genetic architecture of the murine serum metabolome reveals carboxyl esterases as master regulators of circulating fatty acid metabolism", "title_text": "Genetic architecture of the murine serum metabolome reveals carboxyl esterases as master regulators of circulating fatty acid metabolism", "type": "peer-reviewed", "updated_at": "2026-11-04T12:20:44Z", "url": "https://research.draconitic.com/paper/8drvyh2zmtr58", "venue": "PLOS Genetics", "versions": [] }