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Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality
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 spe...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564198/ https://www.ncbi.nlm.nih.gov/pubmed/26352407 http://dx.doi.org/10.1371/journal.pgen.1005487 |
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author | 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 |
author_facet | 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 |
author_sort | Raffler, Johannes |
collection | PubMed |
description | 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 (1)H 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. |
format | Online Article Text |
id | pubmed-4564198 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-45641982015-09-17 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 PLoS Genet Research Article 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 (1)H 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. Public Library of Science 2015-09-09 /pmc/articles/PMC4564198/ /pubmed/26352407 http://dx.doi.org/10.1371/journal.pgen.1005487 Text en © 2015 Raffler et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article 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 |
title | Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality |
title_full | Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality |
title_fullStr | Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality |
title_full_unstemmed | Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality |
title_short | Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality |
title_sort | genome-wide association study with targeted and non-targeted nmr metabolomics identifies 15 novel loci of urinary human metabolic individuality |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564198/ https://www.ncbi.nlm.nih.gov/pubmed/26352407 http://dx.doi.org/10.1371/journal.pgen.1005487 |
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