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 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.
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Johannes
J
Raffler
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Nele
N
Friedrich
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Matthias
M
Arnold
Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Tim
T
Kacprowski
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Rico
R
Rueedi
Research Unit Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Elisabeth
E
Altmaier
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Sven
S
Bergmann
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Kathrin
K
Budde
Research Unit Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Christian
C
Gieger
Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Georg
G
Homuth
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Maik
M
Pietzner
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Werner
W
Römisch-Margl
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
Konstantin
K
Strauch
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany; Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Henry
H
Völzke
Research Unit Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Melanie
M
Waldenberger
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Henri
H
Wallaschofski
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Matthias
M
Nauck
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany; Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Uwe
U
Völker
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Gabi
G
Kastenmüller
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Doha, Qatar.
Karsten
K
Suhre
D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D055432:Metabolomics; D066244:Proton Magnetic Resonance Spectroscopy; D040641:Quantitative Trait Loci; D014556:Urine