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

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

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.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / genetics
  • Acetyltransferases / metabolism
  • Alkaline Phosphatase / genetics
  • Alkaline Phosphatase / metabolism
  • Biomarkers / urine
  • Biotransformation / genetics*
  • Cohort Studies
  • Cytochrome P-450 CYP2D6 / genetics
  • Genome-Wide Association Study
  • Humans
  • Inactivation, Metabolic
  • Kidney / cytology
  • Kidney / metabolism*
  • Metoprolol / pharmacokinetics
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*
  • Renal Insufficiency, Chronic / genetics
  • Renal Insufficiency, Chronic / metabolism
  • Renal Insufficiency, Chronic / urine*
  • Urine / physiology
  • Xenobiotics / pharmacokinetics
  • Xenobiotics / urine

Substances

  • Biomarkers
  • Xenobiotics
  • Cytochrome P-450 CYP2D6
  • Acetyltransferases
  • NAT8 protein, human
  • ALPL protein, human
  • Alkaline Phosphatase
  • Metoprolol