title: Human metabolic individuality in biomedical and pharmaceutical research.
abstract: Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.
authors: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Faculty of Biology, Ludwig-Maximilians-Universität, Planegg-Martinsried, Germany.|Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City - Qatar Foundation, Doha, Qatar.
authors: Karsten
authors: K
authors: Suhre
authors: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton UK.
authors: So-Youn
authors: SY
authors: Shin
authors: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Ann-Kristin
authors: AK
authors: Petersen
authors: Metabolon Inc., Durham, North Carolina, USA.
authors: Robert P
authors: RP
authors: Mohney
authors: School of Life Sciences, Oxford Brookes University, Headington, Oxford, UK.
authors: David
authors: D
authors: Meredith
authors: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Department of Genome-oriented Bioinformatics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
authors: Brigitte
authors: B
authors: Wägele
authors: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Elisabeth
authors: E
authors: Altmaier
authors: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton UK.
authors: Panos
authors: P
authors: Deloukas
authors: Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany.
authors: Jeanette
authors: J
authors: Erdmann
authors: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton UK.|Department of Twin Research & Genetic Epidemiology, King's College London, UK.
authors: Elin
authors: E
authors: Grundberg
authors: Department of Twin Research & Genetic Epidemiology, King's College London, UK.
authors: Christopher J
authors: CJ
authors: Hammond
authors: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
authors: Martin Hrabé
authors: MH
authors: de Angelis
authors: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Gabi
authors: G
authors: Kastenmüller
authors: Renal Division, University Hospital Freiburg, Germany.
authors: Anna
authors: A
authors: Köttgen
authors: Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria.
authors: Florian
authors: F
authors: Kronenberg
authors: Department of Twin Research & Genetic Epidemiology, King's College London, UK.
authors: Massimo
authors: M
authors: Mangino
authors: Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Christa
authors: C
authors: Meisinger
authors: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors: Thomas
authors: T
authors: Meitinger
authors: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Department of Genome-oriented Bioinformatics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
authors: Hans-Werner
authors: HW
authors: Mewes
authors: Metabolon Inc., Durham, North Carolina, USA.
authors: Michael V
authors: MV
authors: Milburn
authors: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Cornelia
authors: C
authors: Prehn
authors: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Faculty of Biology, Ludwig-Maximilians-Universität, Planegg-Martinsried, Germany.
authors: Johannes
authors: J
authors: Raffler
authors: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton UK.
authors: Janina S
authors: JS
authors: Ried
authors: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Werner
authors: W
authors: Römisch-Margl
authors: Department of Cardiovascular Sciences, University of Leicester, and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK.
authors: Nilesh J
authors: NJ
authors: Samani
authors: Department of Twin Research & Genetic Epidemiology, King's College London, UK.
authors: Kerrin S
authors: KS
authors: Small
authors: Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.|Klinikum Grosshadern, Munich, Germany.
authors: H-Erich
authors: HE
authors: Wichmann
authors: Department of Twin Research & Genetic Epidemiology, King's College London, UK.
authors: Guangju
authors: G
authors: Zhai
authors: Unit for Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Thomas
authors: T
authors: Illig
authors: Department of Twin Research & Genetic Epidemiology, King's College London, UK.
authors: Tim D
authors: TD
authors: Spector
authors: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Jerzy
authors: J
authors: Adamski
authors: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton UK.
authors: Nicole
authors: N
authors: Soranzo
authors: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Christian
authors: C
authors: Gieger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D035843:Biomedical Research; D001769:Blood / Q000378:metabolism; D002648:Child; D002908:Chronic Disease; D003324:Coronary Artery Disease / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics; D004345:Drug Industry; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008660:Metabolism / Q000235:genetics*; D055432:Metabolomics; D008875:Middle Aged; D010597:Pharmacogenetics; D051437:Renal Insufficiency / Q000235:genetics; D012307:Risk Factors; D054556:Venous Thromboembolism / Q000235:genetics; D055815:Young Adult