Abstract

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10−10) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.

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Acknowledgements

We thank all the Finnish volunteers who participated in the studies. We thank the IT Center for Science and the technology center of the Institute for Molecular Medicine Finland for providing the computational facilities required in this study. The expert technical assistance for statistical analyses provided by A. Vikman, I. Lisinen, V. Aalto and the Genotyping Facilities at the Wellcome Trust Sanger Institute are gratefully acknowledged. The study was supported through funds from The European Community's Seventh Framework Programme (FP7/2007-2013), the BioSHaRE Consortium (261433), the Sigrid Juselius Foundation (251217 to S.R.), the Academy of Finland (137870 to P.S. and 135973 to P.W.), the Responding to Public Health Challenges Research Programme of the Academy of Finland (129269 to M.J.S., 129429 to M.A.-K., 129322 to M.P. and 139635 to V.S.), the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680 to A.P., J. Kaprio, L.P., K.S. and S.R.), the Finnish Foundation for Cardiovascular Research (to M.J.S., M.A.-K., M.P., S.R. and K.H.P), the Jenny and Antti Wihuri Foundation (to A.J.K.), the Instrumentarium Science Foundation (to T.T. and P.W.), the Finnish Cultural Foundation (to T.T. and T.L.), an Aalto University School of Science and Technology researcher training scholarship (to T.T.) and the Wellcome Trust (098051 to A.P.). The Young Finns Study has been financially supported by the Academy of Finland (126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi)), the Social Insurance Institution of Finland, the Turku University Foundation, the Yrjö Jahnsson Foundation, the Emil Aaltonen Foundation (to T.L.), the Medical Research Fund of Tampere University Hospital, the Turku University Hospital Medical Fund, the Juho Vainio Foundation, the Finnish Foundation for Cardiovascular Research (to T.L.) and the Tampere Tuberculosis Foundation (to T.L. and M.K.). The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland (120386, 125876 and 126775 to J.E.), the Finnish Diabetes Research Society, the Novo Nordisk Foundation, the European Science Foundation (EuroSTRESS), the Wellcome Trust (89061/Z/09/Z and 089062/Z/09/Z), the Samfundet Folkhälsan and the Finska Läkaresällskapet. The FINRISK/DILGOM study was supported by the Academy of Finland (118081). Data collection for FinnTwin12 and FinnTwin16 were supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (AA-12502, AA-09203 and AA-08315 to R.J.R. and AA-15416 to D.M.D.) and the Academy of Finland (100499, 205585, 118555 and 141054 (Skidi-Kids) to J. Kaprio). The Finnish Twin cohorts are also supported by the Novo Nordisk Foundation, the Diabetes Research Foundation, Biomedicum Helsinki and Helsinki University Central Hospital grants (all to K.H.P.). NFBC1966 received financial support from the Academy of Finland (104781, 120315, 129269, 1114194, 139900 and SALVE to M.-R.J. and Center of Excellence in Complex Disease Genetics to L.P.), University Hospital Oulu, Biocenter, University of Oulu (75617 to M.-R.J. and M.J.S.), the European Commission EURO-BLCS Framework 5 award (QLG1-CT-2000-01643 to M.-R.J.), the US National Heart, Lung, and Blood Institute (NHLBI) (5R01HL087679), the US National Institute of Mental Health (NIMH) (1RL1MH083268), European Network for Genetic and Genomic Epidemiology (ENGAGE) (HEALTH-F4-2007-201413 to L.P. and M.-R.J.), the MRC UK (G0500539, G0600705 and PrevMetSyn/Salve to M.-R.J.) and the Wellcome Trust (GR069224).

Author information

Author notes

    • Leena Peltonen

    Deceased.

    • Johannes Kettunen
    •  & Taru Tukiainen

    These authors contributed equally to this work.

Affiliations

  1. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Johannes Kettunen
    • , Taru Tukiainen
    • , Antti-Pekka Sarin
    • , Alfredo Ortega-Alonso
    • , Emmi Tikkanen
    • , Peter Würtz
    • , Kaisa Silander
    • , Kirsi H Pietiläinen
    • , Jaakko Kaprio
    • , Markus Perola
    • , Aarno Palotie
    •  & Samuli Ripatti
  2. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Johannes Kettunen
    • , Antti-Pekka Sarin
    • , Emmi Tikkanen
    • , Kaisa Silander
    • , Antti Jula
    • , Veikko Salomaa
    • , Markus Perola
    •  & Samuli Ripatti
  3. Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

    • Taru Tukiainen
    • , Peter Würtz
    •  & Marjo-Riitta Järvelin
  4. Department of Biomedical Engineering and Computational Science, School of Science, Aalto University, Espoo, Finland.

    • Taru Tukiainen
  5. Computational Medicine Research Group, Institute of Clinical Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.

    • Taru Tukiainen
    • , Antti J Kangas
    • , Pasi Soininen
    • , Peter Würtz
    •  & Mika Ala-Korpela
  6. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Alfredo Ortega-Alonso
    • , Richard J Rose
    •  & Jaakko Kaprio
  7. Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland.

    • Leo-Pekka Lyytikäinen
    •  & Terho Lehtimäki
  8. Nuclear Magnetic Resonance (NMR) Metabonomics Laboratory, Department of Biosciences, University of Eastern Finland, Kuopio, Finland.

    • Pasi Soininen
    •  & Mika Ala-Korpela
  9. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.

    • Danielle M Dick
  10. Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, USA.

    • Richard J Rose
  11. Department of Internal Medicine, Clinical Research Center, University of Oulu, Oulu, Finland.

    • Markku J Savolainen
    •  & Mika Ala-Korpela
  12. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Markku J Savolainen
    • , Marjo-Riitta Järvelin
    •  & Mika Ala-Korpela
  13. Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland.

    • Jorma Viikari
  14. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.

    • Mika Kähönen
  15. Department of Medicine, Division of Internal Medicine, Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland.

    • Kirsi H Pietiläinen
  16. Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.

    • Kirsi H Pietiläinen
  17. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

    • Michael Inouye
  18. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

    • Michael Inouye
  19. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  20. Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.

    • Mark I McCarthy
  21. Unit of Chronic Disease Epidemiology and Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Johan Eriksson
  22. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Johan Eriksson
  23. Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.

    • Johan Eriksson
  24. Folkhälsan Research Centre, Helsinki, Finland.

    • Johan Eriksson
  25. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

    • Olli T Raitakari
  26. Department of Clinical Physiology, Turku University Hospital, Turku, Finland.

    • Olli T Raitakari
  27. Department of Mental Health and Alcohol Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Kaprio
  28. Medical Research Council (MRC) Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK.

    • Marjo-Riitta Järvelin
  29. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Järvelin
  30. Department of Lifecourse and Services, National Institute of Health and Welfare, Oulu, Finland.

    • Marjo-Riitta Järvelin
  31. Estonian Genome Centre, University of Tartu, Tartu, Estonia.

    • Markus Perola
  32. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.

    • Nelson B Freimer
  33. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Aarno Palotie
    •  & Samuli Ripatti
  34. Department of Medical Genetics, University of Helsinki and the Helsinki University Hospital, Helsinki, Finland.

    • Aarno Palotie
  35. The Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.

    • Aarno Palotie

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Contributions

Experiments were designed by L.P., M.P., M.A.-K., A.P. and S.R. Statistical analyses were performed by J. Kettunen, T.T., A.O.-A., E.T. and L.-P.L. Materials and/or analysis tools were contributed by J. Kettunen, T.T., A.-P.S., P.S., A.J.K., P.W., K.S., D.M.D., R.J.R., M.J.S., J.V., M.K., T.L., K.H.P., M.I.M., A.J., J.E., O.T.R., V.S., J. Kaprio, M.-R.J., N.B.F., M.A.-K., A.P. and S.R. The manuscript was written by J. Kettunen, T.T., A.J.K., M.I., N.B.F., M.A.-K., A.P. and S.R. All authors reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Samuli Ripatti.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Table 1–6 and 8, Supplementary Figures 1–4 and Supplementary Note

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    Supplementary Table 7

    All metabolite associations P < 2.31×10−10

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DOI

https://doi.org/10.1038/ng.1073

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