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.

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Acknowledgements

Acknowledgements We acknowledge the contributions of P. Lichtner, G. Eckstein, G. Fischer, T. Strom and all other members of the Helmholtz Zentrum München genotyping staff in generating the SNP data set, as well as all members of field staff who were involved in the planning and conduct of the MONICA (Monitoring trends and determinants on cardiovascular diseases) and KORA (Kooperative Gesundheitsforschung in der Region Augsburg) studies. The KORA group consists of H. E. Wichmann (speaker), A. Peters, R. Holle, J. John, C.M., T.I. and their co-workers, who are responsible for the design and conduct of the KORA studies. For TwinsUK, we thank the staff from the genotyping facilities at the Wellcome Trust Sanger Institute for sample preparation, quality control and genotyping. G. Fischer (KORA) and G. Surdulescu (TwinsUK) selected the samples; sample handling and shipment was organized by H. Chavez (KORA) and D. Hodgkiss (TwinsUK); and U. Goebel (Helmholtz) provided administrative support. Special thanks go to D. Garcia-West for his role in facilitating this study. We are grateful to the CARDIoGRAM investigators for access to their data set. Finally, we thank all study participants of the KORA and the TwinsUK studies for donating their blood and time. The KORA research platform and the MONICA studies were initiated and financed by the Helmholtz Zentrum München, National Research Center for Environmental Health, funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria. This study was supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). Part of this work was financed by the German National Genome Research Network (NGFNPlus: 01GS0823). Computing resources were made available by the Leibniz Supercomputing Centre of the Bavarian Academy of Sciences and Humanities (HLRB project h1231) and the DEISA Extreme Computing Initiative (project MeMGenA). Part of this research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The TwinsUK study was funded by the Wellcome Trust; the European Community’s Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-201865-GEFOS and (FP7/2007-2013); and the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. T.D.S. is an NIHR Senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant (G20234). Both studies received support from ENGAGE project grant agreement HEALTH-F4-2007-201413. N.J.S. holds a British Heart Foundation Chair, is an NIHR Senior Investigator and is supported by the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease. The authors acknowledge the funding and support of the National Eye Institute via an NIH/CIDR genotyping project (PI: T. Young). Genotyping was also performed by CIDR as part of an NEI/NIH project grant. D.M. received support from the Early Career Researcher Scheme at Oxford Brookes University. J.R. is supported by DFG Graduiertenkolleg ‘GRK 1563, Regulation and Evolution of Cellular Systems’ (RECESS); E.A., by BMBF grant 0315494A (project SysMBo); W.R.-M., by BMBF grant 03IS2061B (project Gani_Med); and B.W., by Era-Net grant 0315442A (project PathoGenoMics). A.K. is supported by the Emmy Noether Programme of the German Research Foundation (DFG grant KO-3598/2-1) and F.K., by grants from the ‘Genomics of Lipid-associated Disorders (GOLD)’ of the Austrian Genome Research Programme (GEN-AU). N.S. is supported by the Wellcome Trust (core grant number 091746/Z/10/Z).

Author information

Author notes

    • So-Youn Shin
    • , Ann-Kristin Petersen
    • , Nicole Soranzo
    •  & Christian Gieger

    These authors contributed equally to this work.

Affiliations

  1. Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany

    • Karsten Suhre
    • , Brigitte Wägele
    • , Elisabeth Altmaier
    • , Gabi Kastenmüller
    • , Hans-Werner Mewes
    • , Johannes Raffler
    •  & Werner Römisch-Margl
  2. Faculty of Biology, Ludwig-Maximilians-Universität, Großhaderner Str. 2, 82152 Planegg-Martinsried, Germany

    • Karsten Suhre
    •  & Johannes Raffler
  3. Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, PO Box 24144, Doha, State of Qatar

    • Karsten Suhre
  4. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK

    • So-Youn Shin
    • , Panos Deloukas
    • , Elin Grundberg
    •  & Nicole Soranzo
  5. Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany

    • Ann-Kristin Petersen
    • , Janina S. Ried
    •  & Christian Gieger
  6. Metabolon Inc., Durham, PO Box 110407, Research Triangle Park, North Carolina 27709, USA

    • Robert P. Mohney
    •  & Michael V. Milburn
  7. School of Life Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UK

    • David Meredith
  8. Department of Genome-oriented Bioinformatics, Life and Food Science Center Weihenstephan, Technische Universität München, Alte Akademie 1, 85354 Freising, Germany

    • Brigitte Wägele
    •  & Hans-Werner Mewes
  9. Universität zu Lübeck, Medizinische Klinik II, Ratzeburger Allee 160, 23538 Lübeck, Germany

    • Jeanette Erdmann
  10. Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas' Hospital Campus, 1st Floor South Wing Block, 4 Westminster Bridge Road, London SE1 7EH, UK

    • Elin Grundberg
    • , Christopher J. Hammond
    • , Massimo Mangino
    • , Kerrin S. Small
    • , Guangju Zhai
    •  & Tim D. Spector
  11. Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany

    • Martin Hrabé de Angelis
    • , Cornelia Prehn
    •  & Jerzy Adamski
  12. Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Alte Akademie 1, 85354 Freising, Germany

    • Martin Hrabé de Angelis
    •  & Jerzy Adamski
  13. Renal Division, University Hospital Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany

    • Anna Köttgen
  14. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Christoph Probst Platz 1, 6020 Innsbruck, Austria

    • Florian Kronenberg
  15. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany

    • Christa Meisinger
  16. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany

    • Thomas Meitinger
  17. Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675 München, Germany

    • Thomas Meitinger
  18. Department of Cardiovascular Sciences, University of Leicester and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, University Road, Leicester LE1 7RH, UK

    • Nilesh J. Samani
  19. Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany

    • H. -Erich Wichmann
  20. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Geschwister-Scholl-Platz 1, 80539 München, Germany

    • H. -Erich Wichmann
  21. Klinikum Grosshadern, Marchioninistraße 15, 81377 München, Germany

    • H. -Erich Wichmann
  22. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany

    • Thomas Illig

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  1. CARDIoGRAM

    A list of authors and their affiliations appears in Supplementary Information.

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Contributions

Designed the study: J.A., C.G., T.I., D.M., N.S. and K.S. Conducted the experiments: D.M., M.V.M. and R.P.M. Analysed the data: J.A., E.A., C.G., G.K., A.K., F.K., C.M., D.M., A.-K.P., C.P., J.R., J.S.R., W.R.-M., S.-Y.S., K.S. and B.W. Provided material, data or analysis tools: the CARDIoGRAM consortium, P.D., J.E., E.G., C.J.H., M.H.d.A., T.I., M.M., T.M., H.-W.M., N.J.S., K.S.S., T.D.S., H.-E.W. and G.Z. Wrote the paper: C.G., N.S. and K.S. All authors read the paper and contributed to its final form.

Competing interests

M.V.M. and R.P.M. are employees of Metabolon Inc.

Corresponding authors

Correspondence to Karsten Suhre or Nicole Soranzo.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Tables 1-8 (see separate files for Supplementary Tables 2A and 2B), Supplementary References, a listing of the CARDIoGRAM consortium and funding and Supplementary Figures 1-4.

Zip files

  1. 1.

    Supplementary Data

    This file contains Supplementary Table 2a, which contains the KORA.best.ratios data set and Supplementary Table 2b, which contains the TwinsUK.best.ratios data set. These file were replace on 12 September 2011 as the previous versions seen online had corrupted.

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DOI

https://doi.org/10.1038/nature10354

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