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Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Author

Listed:
  • Johannes Kettunen

    (Computational Medicine, Faculty of Medicine, University of Oulu
    National Institute for Health and Welfare
    NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland
    Biocenter Oulu, University of Oulu)

  • Ayşe Demirkan

    (Leiden University Medical Center
    Erasmus Medical Center
    Present address: LUMC, Building 2, Einthovenweg 20, 2333 ZC Leiden)

  • Peter Würtz

    (Computational Medicine, Faculty of Medicine, University of Oulu)

  • Harmen H.M. Draisma

    (VU University Amsterdam
    EMGO Institute for Health and Care Research
    Neuroscience Campus Amsterdam)

  • Toomas Haller

    (Estonian Genome Center, University of Tartu)

  • Rajesh Rawal

    (Research Unit of Molecular Epidemiology, Helmholtz Zentrum München
    Institute of Epidemiology II, Helmholtz Zentrum München)

  • Anika Vaarhorst

    (Leiden University Medical Center)

  • Antti J. Kangas

    (Computational Medicine, Faculty of Medicine, University of Oulu)

  • Leo-Pekka Lyytikäinen

    (Fimlab Laboratories, University of Tampere School of Medicine, Tampere University)

  • Matti Pirinen

    (Institute for Molecular Medicine (FIMM), University of Helsinki)

  • René Pool

    (VU University Amsterdam
    EMGO Institute for Health and Care Research)

  • Antti-Pekka Sarin

    (National Institute for Health and Welfare
    Institute for Molecular Medicine (FIMM), University of Helsinki)

  • Pasi Soininen

    (Computational Medicine, Faculty of Medicine, University of Oulu
    NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland)

  • Taru Tukiainen

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Harvard Medical School)

  • Qin Wang

    (Computational Medicine, Faculty of Medicine, University of Oulu
    NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland)

  • Mika Tiainen

    (Computational Medicine, Faculty of Medicine, University of Oulu
    NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland)

  • Tuulia Tynkkynen

    (Computational Medicine, Faculty of Medicine, University of Oulu
    NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland)

  • Najaf Amin

    (Erasmus Medical Center)

  • Tanja Zeller

    (German Center for Cardiovascular Research (DZHK e.V.)
    University Heart Center Hamburg, Clinic of general and interventional Cardiology)

  • Marian Beekman

    (Leiden University Medical Center)

  • Joris Deelen

    (Leiden University Medical Center)

  • Ko Willems van Dijk

    (Leiden University Medical Center
    Leiden University Medical Center
    Present address: LUMC, Building 2, Einthovenweg 20, 2333 ZC Leiden)

  • Tõnu Esko

    (Estonian Genome Center, University of Tartu)

  • Jouke-Jan Hottenga

    (VU University Amsterdam
    EMGO Institute for Health and Care Research)

  • Elisabeth M van Leeuwen

    (Erasmus Medical Center)

  • Terho Lehtimäki

    (Fimlab Laboratories, University of Tampere School of Medicine, Tampere University)

  • Evelin Mihailov

    (Estonian Genome Center, University of Tartu)

  • Richard J. Rose

    (Hjelt Institute, University of Helsinki
    Indiana University)

  • Anton J.M. de Craen

    (Leiden University Medical Center)

  • Christian Gieger

    (Research Unit of Molecular Epidemiology, Helmholtz Zentrum München
    Institute of Epidemiology II, Helmholtz Zentrum München)

  • Mika Kähönen

    (University of Tampere and Tampere, University Hospital)

  • Markus Perola

    (National Institute for Health and Welfare
    Estonian Genome Center, University of Tartu
    Institute for Molecular Medicine (FIMM), University of Helsinki)

  • Stefan Blankenberg

    (German Center for Cardiovascular Research (DZHK e.V.)
    University Heart Center Hamburg, Clinic of general and interventional Cardiology)

  • Markku J. Savolainen

    (Biocenter Oulu, University of Oulu
    Medical Research Center, Internal Medicine, Oulu University Hospital, University of Oulu)

  • Aswin Verhoeven

    (Center for Proteomics and Metabolomics, Leiden University Medical Center)

  • Jorma Viikari

    (University of Turku and Turku University Hospital)

  • Gonneke Willemsen

    (VU University Amsterdam
    EMGO Institute for Health and Care Research)

  • Dorret I. Boomsma

    (VU University Amsterdam
    EMGO Institute for Health and Care Research)

  • Cornelia M. van Duijn

    (Erasmus Medical Center)

  • Johan Eriksson

    (National Institute for Health and Welfare
    University of Helsinki
    Folkhälsan Research Centre, Helsingfors Universitet)

  • Antti Jula

    (National Institute for Health and Welfare)

  • Marjo-Riitta Järvelin

    (Biocenter Oulu, University of Oulu
    MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London
    Center for Life Course and Systems Epidemiology, Faculty of Medicine, University of Oulu
    Unit of Primary Care, Oulu University Hospital)

  • Jaakko Kaprio

    (Institute for Molecular Medicine (FIMM), University of Helsinki
    Hjelt Institute, University of Helsinki
    National Institute for Health and Welfare)

  • Andres Metspalu

    (Estonian Genome Center, University of Tartu)

  • Olli Raitakari

    (Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku
    Turku University Hospital)

  • Veikko Salomaa

    (National Institute for Health and Welfare)

  • P. Eline Slagboom

    (Leiden University Medical Center)

  • Melanie Waldenberger

    (Research Unit of Molecular Epidemiology, Helmholtz Zentrum München
    Institute of Epidemiology II, Helmholtz Zentrum München)

  • Samuli Ripatti

    (National Institute for Health and Welfare
    Institute for Molecular Medicine (FIMM), University of Helsinki
    Hjelt Institute, University of Helsinki
    Human Genetics, Wellcome Trust Sanger Institute)

  • Mika Ala-Korpela

    (Computational Medicine, Faculty of Medicine, University of Oulu
    NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland
    Biocenter Oulu, University of Oulu
    Oulu University Hospital)

Abstract

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.

Suggested Citation

  • Johannes Kettunen & Ayşe Demirkan & Peter Würtz & Harmen H.M. Draisma & Toomas Haller & Rajesh Rawal & Anika Vaarhorst & Antti J. Kangas & Leo-Pekka Lyytikäinen & Matti Pirinen & René Pool & Antti-Pek, 2016. "Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA," Nature Communications, Nature, vol. 7(1), pages 1-9, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11122
    DOI: 10.1038/ncomms11122
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    Cited by:

    1. Anna Halama & Shaza Zaghlool & Gaurav Thareja & Sara Kader & Wadha Al Muftah & Marjonneke Mook-Kanamori & Hina Sarwath & Yasmin Ali Mohamoud & Nisha Stephan & Sabine Ameling & Maja Pucic Baković & Jan, 2024. "A roadmap to the molecular human linking multiomics with population traits and diabetes subtypes," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. María Gordillo-Marañón & Magdalena Zwierzyna & Pimphen Charoen & Fotios Drenos & Sandesh Chopade & Tina Shah & Jorgen Engmann & Nishi Chaturvedi & Olia Papacosta & Goya Wannamethee & Andrew Wong & Ree, 2021. "Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    3. Gemma L. Clayton & Maria Carolina Borges & Deborah A. Lawlor, 2024. "The impact of reproductive factors on the metabolic profile of females from menarche to menopause," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Hamzeh M. Tanha & Dale R. Nyholt, 2022. "Genetic analyses identify pleiotropy and causality for blood proteins and highlight Wnt/β-catenin signalling in migraine," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Michael G. Levin & Noah L. Tsao & Pankhuri Singhal & Chang Liu & Ha My T. Vy & Ishan Paranjpe & Joshua D. Backman & Tiffany R. Bellomo & William P. Bone & Kiran J. Biddinger & Qin Hui & Ozan Dikilitas, 2022. "Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Leonardo Bottolo & Marco Banterle & Sylvia Richardson & Mika Ala‐Korpela & Marjo‐Riitta Järvelin & Alex Lewin, 2021. "A computationally efficient Bayesian seemingly unrelated regressions model for high‐dimensional quantitative trait loci discovery," Journal of the Royal Statistical Society Series C, Royal Statistical Society, vol. 70(4), pages 886-908, August.

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