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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.

Genome-wide association study with targeted and non-targeted NMR metabolomics identifies 15 novel loci of urinary human metabolic individuality.

PLoS Genet. 11:e1005487 (2015)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Zeitschrift PLoS Genetics
Quellenangaben Band: 11, Heft: 9, Seiten: , Artikelnummer: e1005487 Supplement: ,
Verlag Public Library of Science (PLoS)
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Bioinformatics and Systems Biology (IBIS)
Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
POF Topic(s) 30505 - New Technologies for Biomedical Discoveries
30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Enabling and Novel Technologies
Genetics and Epidemiology
PSP-Element(e) G-503700-001
G-504091-004
G-504091-001
G-504100-001
G-503700-005
G-504090-001
PubMed ID 26352407
DOI 10.1371/journal.pgen.1005487
WOS ID WOS:000362269000016
Scopus ID 84943579561
Erfassungsdatum 2015-09-11
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