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Urinary Metabolite GWAS Leads to Risk Variants, Potential Markers of Kidney Disease

NEW YORK – A team led by researchers at the University of Freiburg in Germany has identified ties between urine metabolite levels and common genetic variants, laying the foundation for a more refined view of human metabolic processes and the tissues in which they take place.

In a study published in Nature Genetics on Monday, the researchers performed a genome-wide association study involving 1,627 individuals with diminished kidney function, searching for genetic loci coinciding with urine metabolite concentrations. The metabolic GWAS (mGWAS) led to 240 loci with apparent ties to urine metabolite concentrations, while their follow-up fine-mapping and single-cell expression analyses helped focus in on potential disease-causing genes, the cell types involved, and the urinary metabolites that may flag genetic predisposition to kidney disease.

The team noted that this collection could offer a window into metabolite absorption, distribution, metabolism, and excretion (ADME) — the processes that collectively mediate metabolite concentrations — as well as the compounds produced en route to these products of metabolism.

"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," senior author Anna Köttgen, a genetic epidemiologist at the University of Freiburg, and her colleagues wrote.

Prior studies suggest that tissues from several key organs — from the liver and kidneys to the blood and intestinal tract — have a part to play in different aspects of ADME, the investigators explained. But they suspected that there might be much more to learn about metabolism by testing urine samples in individuals with lower-than-usual metabolite detoxification and transport in the kidney's proximal tubules due to existing kidney conditions.

Moreover, while mGWAS "can provide novel insights into human physiology, inborn errors of metabolisms, and complex traits and diseases," the authors explained, most of the studies done so far have focused on blood metabolites in individuals from the general population.

For their new mGWAS, the researchers took a look at genotypes spanning some 2.6 million SNPs in 1,221 individuals from the German Chronic Kidney Disease (GCKD) study, searching for variants with ties to urine levels for 1,172 metabolites assessed by mass spectrometry.

The team's analysis highlighted 240 metabolite-linked loci — associations verified using data for another 406 GCKD patients. It also extended these results to a population cohort, shoring up a subset of the associations in almost 1,000 individuals from the "Study of Health in Pomerania-Trend" population.

Bringing in human RNA sequence data and single-cell mouse kidney cell gene expression data made it possible to fine-map metabolite quantitative trait loci (mQTL), find related cell types, and uncover functional clues for the variants identified. For example, the authors saw dozens of genes with enhanced expression in kidney and other tissue types that coincided with urine metabolite levels, and focused in on regulatory roles for some non-coding variants.

When they considered the newly-identified mQTLs in conjunction with UK Biobank data, meanwhile, the researchers found possible urinary metabolite markers that correspond to genetic risk of kidney disease.

"The comprehensive list of genetic targets and their corresponding substrates reveals novel insights into human ADME processes and biotransformation reactions," the authors explained, "and is relevant to basic science, clinical medicine, and pharmaceutical research."