Genetic architecture of the murine serum metabolome reveals carboxyl esterases as master regulators of circulating fatty acid metabolism
7 affiliations
- 1RTI International, Research Triangle Park, North Carolina, United States of America
- 2The Jackson Laboratory, Bar Harbor, Maine, United States of America
- 3Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, Colorado, United States of America
- 4Omix Technologies Inc, Aurora, Colorado, United States of America
- 5Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America
- 6Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- 7Canadian Blood Services, Ottawa, Ontario, Canada
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.
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BibTeX
@article{keele2026genetic,
title = {{Genetic architecture of the murine serum metabolome reveals carboxyl esterases as master regulators of circulating fatty acid metabolism}},
author = {Gregory R. Keele and Travis Nemkov and Ariel M. Hay and Matthew Vincent and Callan O'Connor and Daniel Stephenson and Grier P. Page and James C. Zimring and Gary A. Churchill and Angelo D’Alessandro},
journal = {PLOS Genetics},
year = {2026},
month = nov,
doi = {10.1371/journal.pgen.1012223},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012223},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Genetic architecture of the murine serum metabolome reveals carboxyl esterases as master regulators of circulating fatty acid metabolism
AU - Gregory R. Keele
AU - Travis Nemkov
AU - Ariel M. Hay
AU - Matthew Vincent
AU - Callan O'Connor
AU - Daniel Stephenson
AU - Grier P. Page
AU - James C. Zimring
AU - Gary A. Churchill
AU - Angelo D’Alessandro
PY - 2026
DA - 2026/11/02
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012223
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012223
AB - 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.
SN - 1553-7404
ER -