Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality

PLoS Genet. 2015 Sep 9;11(9):e1005487. doi: 10.1371/journal.pgen.1005487. eCollection 2015 Sep.


Genome-wide association studies with metabolic traits (mGWAS) uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs) contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3). Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13), pulmonary hypertension (CPS1), and ischemic stroke (XYLB). By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular mechanisms involved in the etiology of diseases.

MeSH terms

  • Chromosome Mapping
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Metabolomics*
  • Proton Magnetic Resonance Spectroscopy
  • Quantitative Trait Loci
  • Urine*

Grant support

SHIP (Study of Health in Pomerania) is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the German Ministry of Education and Research (BMBF, (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the University Medicine Greifswald as well as a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. Generation of genome-wide data in SHIP has also been supported by the BMBF (grant no. 03ZIK012). The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München - German Research Center for Environmental Health, which is funded by the BMBF and by the Federal State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. MA is supported by the Helmholtz Cross Program Activity “Metabolic Dysfunction and Human Diseases”. TK and JR were supported by the GANI_MED project funded by the BMBF and the State of Mecklenburg-West Pomerania (grant no. 03IS2061A). SB received funding from the Swiss Institute of Bioinformatics and the Swiss National Science Foundation (grant no. FN 310030_152724/1). WRM is supported by the Helmholtz Cross Program Initiative “Personalized Medicine (iMed)”. KSu is supported by the “Biomedical Research Program” funds at Weill Cornell Medical College in Qatar, a program funded by the Qatar Foundation ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.