| Literature DB >> 31959995 |
Pascal Schlosser1, Yong Li1, Peggy Sekula1, Johannes Raffler2, Franziska Grundner-Culemann1, Maik Pietzner3,4, Yurong Cheng1, Matthias Wuttke1,5, Inga Steinbrenner1, Ulla T Schultheiss1,5, Fruzsina Kotsis1,5, Tim Kacprowski4,6,7, Lukas Forer8, Birgit Hausknecht9, Arif B Ekici10, Matthias Nauck3,4, Uwe Völker4,6, Gerd Walz5, Peter J Oefner11, Florian Kronenberg8, Robert P Mohney12, Michael Köttgen5, Karsten Suhre13, Kai-Uwe Eckardt9,14, Gabi Kastenmüller2, Anna Köttgen15.
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.Entities:
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Year: 2020 PMID： 31959995 PMCID： PMC7484970 DOI： 10.1038/s41588-019-0567-8
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330