Open AccessGenetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans
Author(s) -
Pascal Schlosser,
Yong Li,
Peggy Sekula,
Johannes Raffler,
Franziska Grundner-Culemann,
Maik Pietzner,
Yu-Rong Cheng,
Matthias Wuttke,
Inga Steinbrenner,
Ulla T. Schultheiss,
Fruzsina Kotsis,
Tim Kacprowski,
Lukas Forer,
Birgit Hausknecht,
Arif B. Ekici,
Matthias Nauck,
Uwe Völker,
Gckd Investigators,
Gerd Walz,
Peter J. Oefner,
Florian Kronenberg,
Robert P. Mohney,
Michael Köttgen,
Karsten Suhre,
KaiUwe Eckardt,
Gabi Kastenmüller,
Anna Köttgen
Publication year - 2020
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-019-0567-8
Subject(s) - biology , adme , genome wide association study , computational biology , metabolite , metabolomics , genetics , gene , biobank , genome , toxicogenomics , single nucleotide polymorphism , bioinformatics , gene expression , genotype , biochemistry , in vitro
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.