Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits
Abstract: Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene–metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models of human metabolism) and one experimental proof of principle) provided orthogonal evidence that studies of rare, damaging variants in the heterozygous state permit inferences concordant with those from inborn errors of metabolism. Allelic series of functional variants in transporters responsible for transcellular sulfate reabsorption (SLC13A1, SLC26A1) exhibited graded effects on plasma sulfate and human height and pinpointed alleles associated with increased odds of diverse musculoskeletal traits and diseases in the population. This integrative approach can identify new players in incompletely characterized human metabolic reactions and reveal metabolic readouts informative of human traits and diseases
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Notes
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Nature genetics. - 57, 1 (2025) , 193-205, ISSN: 1546-1718
- Event
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Veröffentlichung
- (where)
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Freiburg
- (who)
-
Universität
- (when)
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2025
- Creator
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Scherer, Nora
Borisov, Oleg V.
Cheng, Yurong
Schlosser, Pascal
Wuttke, Matthias
Haug, Stefan Peter Gustav
Li, Yong
Telkämper, Fabian
Patil, Suraj
Berger, Urs
Sekula, Peggy
Hoppmann, Anselm
Schultheiß, Ulla Teresa
Schmidts, Miriam
Köttgen, Michael
Grünert, Sarah
Hertel, Johannes
Köttgen, Anna
- DOI
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10.1038/s41588-024-01965-7
- URN
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urn:nbn:de:bsz:25-freidok-2621040
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.08.2025, 7:32 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Scherer, Nora
- Borisov, Oleg V.
- Cheng, Yurong
- Schlosser, Pascal
- Wuttke, Matthias
- Haug, Stefan Peter Gustav
- Li, Yong
- Telkämper, Fabian
- Patil, Suraj
- Berger, Urs
- Sekula, Peggy
- Hoppmann, Anselm
- Schultheiß, Ulla Teresa
- Schmidts, Miriam
- Köttgen, Michael
- Grünert, Sarah
- Hertel, Johannes
- Köttgen, Anna
- Universität
Time of origin
- 2025
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