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Nat Genet. 2020 Feb;52(2):167-176. doi: 10.1038/s41588-019-0567-8. Epub 2020 Jan 20.

Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans.

Author information

Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
German Center for Cardiovascular Research (DZHK e.V.), partner site Greifswald, Greifswald, Germany.
Department of Medicine IV: Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Research Group on Computational Systems Medicine, Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.
Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
Metabolon Inc., Durham, NC, USA.
Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar.
Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.


The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function. The 240 unique metabolite-locus associations (metabolite quantitative trait loci, mQTLs) that were identified and replicated highlight novel candidate substrates for transport proteins. The identified genes are enriched in ADME-relevant tissues and cell types, and they reveal novel candidates for biotransformation and detoxification reactions. Fine mapping of mQTLs and integration with single-cell gene expression permitted the prioritization of causal genes, functional variants and target cell types. The combination of mQTLs with genetic and health information from 450,000 UK Biobank participants illuminated metabolic mediators, and hence, novel urinary biomarkers of disease risk. This comprehensive resource of genetic targets and their substrates is informative for ADME processes in humans and is relevant to basic science, clinical medicine and pharmaceutical research.


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