Scherer, Nora and Faessler, Daniel and Borisov, Oleg and Cheng, Yurong and Schlosser, Pascal and Wuttke, Matthias and Haug, Stefan and Li, Yong and Telkaemper, Fabian and Patil, Suraj and Meiselbach, Heike and Wong, Casper and Berger, Urs and Sekula, Peggy and Hoppmann, Anselm and Schultheiss, Ulla T. and Mozaffari, Sahar and Xi, Yannan and Graham, Robert and Schmidts, Miriam and Koettgen, Michael and Oefner, Peter J. and Knauf, Felix and Eckardt, Kai-Uwe and Gruenert, Sarah C. and Estrada, Karol and Thiele, Ines and Hertel, Johannes and Koettgen, Anna (2025) Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits. NATURE GENETICS, 57 (1). ISSN 1061-4036, 1546-1718
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | KIDNEY-DISEASE GCKD; TRANSPORT; SULFATE; PLASMA; SLC13A1; PROTEIN; ASSOCIATIONS; GENOTYPE; DATABASE; ATLAS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Mar 2026 09:12 |
| Last Modified: | 30 Mar 2026 09:12 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67928 |
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