1. Untargeted Metabolome Quantitative Trait Locus Mapping Associates Variation in Urine Glycerate to Mutant Glycerate Kinase
- Author
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Karène Argoud, Yulan Wang, Dominique Gauguier, Steve Chappell Mitchell, Benjamin J. Blaise, Timothy M. D. Ebbels, John C. Lindon, Pamela J. Kaisaki, Jean-Baptiste Cazier, Kirill Veselkov, Jeremy K. Nicholson, Elaine Holmes, Tsz M. Tsang, James Scott, Marie-Thérèse Bihoreau, Marc-Emmanuel Dumas, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, ISA - Centre de RMN à très hauts champs, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biomolecular Medicine, Imperial College London, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, The Chinese Academy of Sciences, Metabometrix Ltd, Imperial Incubator, Department of Vascular Science, Department of Surgery and Cancer, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Wellcome Trust (066786, 090532/Z/09/Z), European Commission (LSHG-CT-2006-037683, FP7/2007-2013, HEALTH-F4-2010-241504), Institut National du Cancer INCa-2008-060, Agence Nationale pour la Recherche (ANR-08-GENOPAT-030 , ANR-07-JCJC-0042), Wellcome senior fellowship in basic biomedical science (057733), European Project, University of Oxford [Oxford], Centre de RMN à très hauts champs, Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
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Male ,Quantitative Trait Loci ,Locus (genetics) ,Biology ,Quantitative trait locus ,Glyceric Acids ,glycerate ,Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Metabolomics ,quantitative trait locus ,NMR spectroscopy ,[CHIM.ANAL]Chemical Sciences/Analytical chemistry ,Metabolome ,Animals ,Computer Simulation ,genetics ,glycerate kinase ,Nuclear Magnetic Resonance, Biomolecular ,030304 developmental biology ,Genetic association ,Genetics ,Analysis of Variance ,Mice, Inbred BALB C ,0303 health sciences ,METABONOMICS ,Chromosome Mapping ,Genomics ,General Chemistry ,Quantitative genetics ,INSULIN-RESISTANT MICE ,Human genetics ,3. Good health ,Phosphotransferases (Alcohol Group Acceptor) ,SYSTEMS BIOLOGY ,Lod Score ,functional genomics ,030217 neurology & neurosurgery ,Glycerate kinase - Abstract
With successes of genome-wide association studies, molecular phenotyping systems are developed to identify genetically determined disease-associated biomarkers. Genetic studies of the human metabolome are emerging but exclusively apply targeted approaches, which restricts the analysis to a limited number of well-known metabolites. We have developed novel technical and statistical methods for systematic and automated quantification of untargeted NMR spectral data designed to perform robust and accurate quantitative trait locus (QTL) mapping of known and previously unreported molecular compounds of the metabolome. For each spectral peak, six summary statistics were calculated and independently tested for evidence of genetic linkage in a cohort of F2 (129S6xBALB/c) mice. The most significant evidence of linkages were obtained with NMR signals characterizing the glycerate (LOD10-42) at the mutant glycerate kinase locus, which demonstrate the power of metabolomics in quantitative genetics to identify the biological function of genetic variants. These results provide new insights into the resolution of the complex nature of metabolic regulations and novel analytical techniques that maximize the full utilization of metabolomic spectra in human genetics to discover mappable disease-associated biomarkers. © 2011 American Chemical Society.
- Published
- 2011
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