title: Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.
abstract: Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1)H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10(-8)) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10(-44)) and lysine (rs8101881, P = 1.2×10(-33)), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland ; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Rico
authors.initials: R
authors.lastname: Rueedi
authors.affiliation: Department of Food-Consumer Interaction, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Mirko
authors.initials: M
authors.lastname: Ledda
authors.affiliation: Investigative Preclinical Toxicology, GlaxoSmithKline R&D, Ware, Herts, United Kingdom.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Nicholls
authors.affiliation: European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom ; Department of Biochemistry & Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Reza M
authors.initials: RM
authors.lastname: Salek
authors.affiliation: Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne, Switzerland.
authors.forename: Pedro
authors.initials: P
authors.lastname: Marques-Vidal
authors.affiliation: Sensonomic Laboratory of Alberto Santos Dumont Research Support Association and IEP Sirio, Libanes Hospital, São Paulo, Brazil ; Edmond and Lily Safra International Institute of Neuroscience of Natal, Natal, Brazil.
authors.forename: Edgard
authors.initials: E
authors.lastname: Morya
authors.affiliation: Department of Radiology and Oncology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sameshima
authors.affiliation: Department of Bioanalytical Sciences, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Montoliu
authors.affiliation: Department of Bioanalytical Sciences, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Laeticia
authors.initials: L
authors.lastname: Da Silva
authors.affiliation: Department of Bioanalytical Sciences, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Collino
authors.affiliation: Department of Bioanalytical Sciences, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: François-Pierre
authors.initials: FP
authors.lastname: Martin
authors.affiliation: Department of Bioanalytical Sciences, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Rezzi
authors.affiliation: European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Christoph
authors.initials: C
authors.lastname: Steinbeck
authors.affiliation: Medical Genetics, GlaxoSmithKline, Philadelphia, Pennsylvania, United States of America.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Waterworth
authors.affiliation: Department of Medicine, Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Gérard
authors.initials: G
authors.lastname: Waeber
authors.affiliation: Department of Medicine, Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland ; Swiss Institute of Bioinformatics, Lausanne, Switzerland ; Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.affiliation: Department of Food-Consumer Interaction, Nestlé Research Center, Lausanne, Switzerland ; Organization for Interdisciplinary Research Projects, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan.
authors.forename: Johannes
authors.initials: J
authors.lastname: Le Coutre
authors.affiliation: Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mooser
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland ; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Bergmann
authors.affiliation: Department of Food-Consumer Interaction, Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Ulrich K
authors.initials: UK
authors.lastname: Genick
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland ; Swiss Institute of Bioinformatics, Lausanne, Switzerland ; Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne, Switzerland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D000818:Animals; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055442:Metabolome / Q000235:genetics*; D055432:Metabolomics; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014556:Urine; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D026923:Amino Acid Transport Systems, Basic; D005647:Fucosyltransferases; D000097631:Galactoside 2-alpha-L-fucosyltransferase; C499489:SLC7A9 protein, human