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

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-Pekka Sarin, Pasi Soininen, Taru Tukiainen, Qin Wang, Mika Tiainen, Tuulia Tynkkynen, Najaf Amin, Tanja Zeller, Marian Beekman, Joris Deelen, Ko Willems van Dijk, Tõnu Esko, Jouke-Jan Hottenga, Elisabeth M van Leeuwen, Terho Lehtimäki, Evelin Mihailov, Richard J. Rose, Anton J.M. de Craen, Christian Gieger, Mika Kähönen, Markus Perola, Stefan Blankenberg, Markku J. Savolainen, Aswin Verhoeven, Jorma Viikari, Gonneke Willemsen, Dorret I. Boomsma, Cornelia M. van Duijn, Johan Eriksson, Antti Jula, Marjo-Riitta Järvelin, Jaakko Kaprio, Andres Metspalu, Olli Raitakari, Veikko Salomaa, P. Eline Slagboom, Melanie Waldenberger, Samuli Ripatti and Mika Ala-Korpela
Additional contact information
Johannes Kettunen: Computational Medicine, Faculty of Medicine, University of Oulu
Ayşe Demirkan: Leiden University Medical Center
Peter Würtz: Computational Medicine, Faculty of Medicine, University of Oulu
Harmen H.M. Draisma: VU University Amsterdam
Toomas Haller: Estonian Genome Center, University of Tartu
Rajesh Rawal: Research Unit of Molecular Epidemiology, 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
Antti-Pekka Sarin: National Institute for Health and Welfare
Pasi Soininen: Computational Medicine, Faculty of Medicine, University of Oulu
Taru Tukiainen: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Qin Wang: Computational Medicine, Faculty of Medicine, University of Oulu
Mika Tiainen: Computational Medicine, Faculty of Medicine, University of Oulu
Tuulia Tynkkynen: Computational Medicine, Faculty of Medicine, University of Oulu
Najaf Amin: Erasmus Medical Center
Tanja Zeller: German Center for Cardiovascular Research (DZHK e.V.)
Marian Beekman: Leiden University Medical Center
Joris Deelen: Leiden University Medical Center
Ko Willems van Dijk: Leiden University Medical Center
Tõnu Esko: Estonian Genome Center, University of Tartu
Jouke-Jan Hottenga: VU University Amsterdam
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
Anton J.M. de Craen: Leiden University Medical Center
Christian Gieger: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München
Mika Kähönen: University of Tampere and Tampere, University Hospital
Markus Perola: National Institute for Health and Welfare
Stefan Blankenberg: German Center for Cardiovascular Research (DZHK e.V.)
Markku J. Savolainen: Biocenter Oulu, 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
Dorret I. Boomsma: VU University Amsterdam
Cornelia M. van Duijn: Erasmus Medical Center
Johan Eriksson: National Institute for Health and Welfare
Antti Jula: National Institute for Health and Welfare
Marjo-Riitta Järvelin: Biocenter Oulu, University of Oulu
Jaakko Kaprio: Institute for Molecular Medicine (FIMM), University of Helsinki
Andres Metspalu: Estonian Genome Center, University of Tartu
Olli Raitakari: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku
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
Samuli Ripatti: National Institute for Health and Welfare
Mika Ala-Korpela: Computational Medicine, Faculty of Medicine, University of Oulu

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11122

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