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

Schlosser P, Li Y, Sekula P, Raffler J, Grundner-Culemann F, Pietzner M, Cheng Y, Wuttke M, Steinbrenner I, Schultheiss UT, Kotsis F, Kacprowski T, Forer L, Hausknecht B, Ekici AB, Nauck M, Voelker U, Walz G, Oefner PJ, Kronenberg F, Mohney RP, Koettgen M, Suhre K, Eckardt KU, Kastenmueller G, Koettgen A (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Nature Genetics Nature Publishing Group

DOI: 10.1038/s41588-019-0567-8

Abstract

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.

Authors with CRIS profile

Arif Bülent Ekici Institute of Human Genetics Kai-Uwe Eckardt Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

Albert-Ludwigs-Universität Freiburg DE Germany (DE) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) DE Germany (DE) Universität Regensburg DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Medizinische Universität Innsbruck AT Austria (AT) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald DE Germany (DE) Weill Cornell Medicine-Qatar (WCM-Q) QA Qatar (QA) Metabolon, Inc. US United States (USA) (US)

How to cite

APA:

Schlosser, P., Li, Y., Sekula, P., Raffler, J., Grundner-Culemann, F., Pietzner, M.,... Koettgen, A. (2020). Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans. Nature Genetics. https://doi.org/10.1038/s41588-019-0567-8

MLA:

Schlosser, Pascal, et al. "Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans." Nature Genetics (2020).

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