title: Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels.
abstract: Metabolites are small molecules involved in cellular metabolism, which can be detected in biological samples using metabolomic techniques. Here we present the results of genome-wide association and meta-analyses for variation in the blood serum levels of 129 metabolites as measured by the Biocrates metabolomic platform. In a discovery sample of 7,478 individuals of European descent, we find 4,068 genome- and metabolome-wide significant (Z-test, P < 1.09 × 10(-9)) associations between single-nucleotide polymorphisms (SNPs) and metabolites, involving 59 independent SNPs and 85 metabolites. Five of the fifty-nine independent SNPs are new for serum metabolite levels, and were followed-up for replication in an independent sample (N = 1,182). The novel SNPs are located in or near genes encoding metabolite transporter proteins or enzymes (SLC22A16, ARG1, AGPS and ACSL1) that have demonstrated biomedical or pharmaceutical importance. The further characterization of genetic influences on metabolic phenotypes is important for progress in biological and medical research.
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, Amsterdam 1081 BT, The Netherlands.|The EMGO+ Institute for Health and Care Research, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.|Neuroscience Campus Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, The Netherlands.
authors.forename: Harmen H M
authors.initials: HHM
authors.lastname: Draisma
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, Amsterdam 1081 BT, The Netherlands.|The EMGO+ Institute for Health and Care Research, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.|BBMRINL: Infrastructure for the Application of Metabolomics Technology in Epidemiology (RP4), S4-P, Postbus 9600, Leiden 2300 RC, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Pool
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstraße 1, Neuherberg 85764, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kobl
authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, VUmc, A.J. Ernststraat 1187, Amsterdam 1081 HL, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstraße 1, Neuherberg 85764, Germany.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Petersen
authors.affiliation: BBMRINL: Infrastructure for the Application of Metabolomics Technology in Epidemiology (RP4), S4-P, Postbus 9600, Leiden 2300 RC, The Netherlands.|Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands.|Netherlands Consortium for Healthy Aging, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anika A M
authors.initials: AAM
authors.lastname: Vaarhorst
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Idil
authors.initials: I
authors.lastname: Yet
authors.affiliation: Estonian Genome Center, University of Tartu, 23b Riia Street, Tartu 51010, Estonia.
authors.forename: Toomas
authors.initials: T
authors.lastname: Haller
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, S4-P, PO Box 9600, Leiden 2300 RC, The Netherlands.|Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands.
authors.forename: Ayşe
authors.initials: A
authors.lastname: Demirkan
authors.affiliation: Estonian Genome Center, University of Tartu, 23b Riia Street, Tartu 51010, Estonia.|Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, 300 Longwood Ave, Boston MA02115, Massachusetts, USA.|Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 2142, USA.|Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 0330, Boston MA 02115, Massachusetts, USA.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane 4006, Australia.
authors.forename: Gu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Böhringer
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, S4-P, PO Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Jan Bert
authors.initials: JB
authors.lastname: van Klinken
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg 85764, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Römisch-Margl
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Ingolstädter Landstraße1, Neuherberg 85764, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Prehn
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Ingolstädter Landstraße1, Neuherberg 85764, Germany.|German Center for Diabetes Research at Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.|Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan 85350, Germany.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Anton J M
authors.initials: AJM
authors.lastname: de Craen
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: van Leeuwen
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, S4-P, PO Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Harish
authors.initials: H
authors.lastname: Dharuri
authors.affiliation: Department of Genetics, CB50, UniversityMedical Center Groningen, University of Groningen, P.O. Box 30001, Groningen 9700 RB, The Netherlands.
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: Department of Genetics, CB50, UniversityMedical Center Groningen, University of Groningen, P.O. Box 30001, Groningen 9700 RB, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, Amsterdam 1081 BT, The Netherlands.|The EMGO+ Institute for Health and Care Research, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Eco J C
authors.initials: EJC
authors.lastname: de Geus
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, Amsterdam 1081 BT, The Netherlands.|The EMGO+ Institute for Health and Care Research, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Jouke Jan
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, Amsterdam 1081 BT, The Netherlands.|The EMGO+ Institute for Health and Care Research, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane 4006, Australia.
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane 4006, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane 4006, Australia.|Statistical and Genomic Epidemiology, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Ave, Kelvin Grove QLD 4059, Queensland, Australia.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane 4006, Australia.
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
authors.affiliation: The EMGO+ Institute for Health and Care Research, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.|Department of Psychiatry, VU University Medical Center, A.J. Ernststraat 1187, Amsterdam 1081 HL, The Netherlands.
authors.forename: Brenda W
authors.initials: BW
authors.lastname: Penninx
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Estonian Genome Center, University of Tartu, 23b Riia Street, Tartu 51010, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: BBMRINL: Infrastructure for the Application of Metabolomics Technology in Epidemiology (RP4), S4-P, Postbus 9600, Leiden 2300 RC, The Netherlands.|Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, S4-P, PO Box 9600, Leiden 2300 RC, The Netherlands.|Department of Endocrinology, Leiden University Medical Center, S4-P, PO Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Ko Willems
authors.initials: KW
authors.lastname: van Dijk
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, S4-P, PO Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Peter A C
authors.initials: PAC
authors.lastname: 't Hoen
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstraße 1, Neuherberg 85764, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich 81377, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane 4006, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, S4-P, PO Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Gert-Jan B
authors.initials: GB
authors.lastname: van Ommen
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg 85764, Germany.|Hannover Unified Biobank, Hannover Medical School, Hannover 30625, Germany.|Institute for Human Genetics, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover 30625, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg 85764, Germany.|Faculty of Biology, Ludwig-Maximilians-Universität, Planegg-Martinsried 82152, Germany.|Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar (WCMC-Q), PO Box 24144, Education City-Qatar Foundation, Doha, Qatar.
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.|Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK.|Oxford National Institute for Health Research Biomedical Research Centre, The Joint Research Office, Block 60, Churchill Hospital, Old Road, Headington OX3 7LE, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstraße 1, Neuherberg 85764, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg 85764, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstraße 1, Neuherberg 85764, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands.
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.affiliation: BBMRINL: Infrastructure for the Application of Metabolomics Technology in Epidemiology (RP4), S4-P, Postbus 9600, Leiden 2300 RC, The Netherlands.|Netherlands Consortium for Healthy Aging, Leiden University Medical Center, Leiden, The Netherlands.|Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, Amsterdam 1081 BT, The Netherlands.|The EMGO+ Institute for Health and Care Research, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.|BBMRINL: Infrastructure for the Application of Metabolomics Technology in Epidemiology (RP4), S4-P, Postbus 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
mesh_terms: D001769:Blood / Q000378:metabolism*; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide