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

Johannes Raffler, Nele Friedrich, Matthias Arnold, Tim Kacprowski, Rico Rueedi, Elisabeth Altmaier, Sven Bergmann, Kathrin Budde, Christian Gieger, Georg Homuth, Maik Pietzner, Werner Römisch-Margl, Konstantin Strauch, Henry Völzke, Melanie Waldenberger, Henri Wallaschofski, Matthias Nauck, Uwe Völker, Gabi Kastenmüller, Karsten Suhre

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere1005487
JournalPLoS Genetics
Volume11
Issue number9
DOIs
Publication statusPublished - 2015
Externally publishedYes

Fingerprint

Metabolomics
Genome-Wide Association Study
metabolomics
Individuality
nuclear magnetic resonance
genome
blood
loci
urine
homeostasis
Urine
Inositol
excretion
metabolite
Homeostasis
myo-inositol
hypertension
etiology
Metabolic Diseases
detoxification

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality. / Raffler, Johannes; Friedrich, Nele; Arnold, Matthias; Kacprowski, Tim; Rueedi, Rico; Altmaier, Elisabeth; Bergmann, Sven; Budde, Kathrin; Gieger, Christian; Homuth, Georg; Pietzner, Maik; Römisch-Margl, Werner; Strauch, Konstantin; Völzke, Henry; Waldenberger, Melanie; Wallaschofski, Henri; Nauck, Matthias; Völker, Uwe; Kastenmüller, Gabi; Suhre, Karsten.

In: PLoS Genetics, Vol. 11, No. 9, e1005487, 2015.

Research output: Contribution to journalArticle

Raffler, J, Friedrich, N, Arnold, M, Kacprowski, T, Rueedi, R, Altmaier, E, Bergmann, S, Budde, K, Gieger, C, Homuth, G, Pietzner, M, Römisch-Margl, W, Strauch, K, Völzke, H, Waldenberger, M, Wallaschofski, H, Nauck, M, Völker, U, Kastenmüller, G & Suhre, K 2015, 'Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality', PLoS Genetics, vol. 11, no. 9, e1005487. https://doi.org/10.1371/journal.pgen.1005487
Raffler, Johannes ; Friedrich, Nele ; Arnold, Matthias ; Kacprowski, Tim ; Rueedi, Rico ; Altmaier, Elisabeth ; Bergmann, Sven ; Budde, Kathrin ; Gieger, Christian ; Homuth, Georg ; Pietzner, Maik ; Römisch-Margl, Werner ; Strauch, Konstantin ; Völzke, Henry ; Waldenberger, Melanie ; Wallaschofski, Henri ; Nauck, Matthias ; Völker, Uwe ; Kastenmüller, Gabi ; Suhre, Karsten. / Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality. In: PLoS Genetics. 2015 ; Vol. 11, No. 9.
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AU - Kacprowski, Tim

AU - Rueedi, Rico

AU - Altmaier, Elisabeth

AU - Bergmann, Sven

AU - Budde, Kathrin

AU - Gieger, Christian

AU - Homuth, Georg

AU - Pietzner, Maik

AU - Römisch-Margl, Werner

AU - Strauch, Konstantin

AU - Völzke, Henry

AU - Waldenberger, Melanie

AU - Wallaschofski, Henri

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