title: Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA.
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.
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.|National Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, Kuopio 70210, Finland.|Biocenter Oulu, University of Oulu, PO Box 5000, FI-90014 Oulu, Finland.
authors.forename: Johannes
authors.identifier: http://orcid.org/0000-0002-3345-491X
authors.initials: J
authors.lastname: Kettunen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Ayşe
authors.initials: A
authors.lastname: Demirkan
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.
authors.forename: Peter
authors.initials: P
authors.lastname: Würtz
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Room 2B-29, 1081 BT Amsterdam, The Netherlands.|EMGO Institute for Health and Care Research, Van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.|Neuroscience Campus Amsterdam, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands.
authors.forename: Harmen H M
authors.initials: HH
authors.lastname: Draisma
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
authors.forename: Toomas
authors.initials: T
authors.lastname: Haller
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rawal
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Anika
authors.initials: A
authors.lastname: Vaarhorst
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Kangas
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere University, Kalevantie 4, Tampere 33014, Finland.
authors.forename: Leo-Pekka
authors.initials: LP
authors.lastname: Lyytikäinen
authors.affiliation: Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum 2, Tukholmankatu 8, Helsinki 00290, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Pirinen
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Room 2B-29, 1081 BT Amsterdam, The Netherlands.|EMGO Institute for Health and Care Research, Van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Pool
authors.affiliation: National Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.|Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum 2, Tukholmankatu 8, Helsinki 00290, Finland.
authors.forename: Antti-Pekka
authors.identifier: http://orcid.org/0000-0002-5753-9782
authors.initials: AP
authors.lastname: Sarin
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, Kuopio 70210, Finland.
authors.forename: Pasi
authors.initials: P
authors.lastname: Soininen
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.|Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 0330, Boston, Massachusetts 02115, USA.
authors.forename: Taru
authors.initials: T
authors.lastname: Tukiainen
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, Kuopio 70210, Finland.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, Kuopio 70210, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Tiainen
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, Kuopio 70210, Finland.
authors.forename: Tuulia
authors.identifier: http://orcid.org/0000-0002-8586-7345
authors.initials: T
authors.lastname: Tynkkynen
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: German Center for Cardiovascular Research (DZHK e.V.), Partner Site Hamburg/Lübeck/Kiel, Martinistraße 52, 20246 Hamburg, Germany.|University Heart Center Hamburg, Clinic of general and interventional Cardiology, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Marian
authors.identifier: http://orcid.org/0000-0003-0585-6206
authors.initials: M
authors.lastname: Beekman
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Joris
authors.identifier: http://orcid.org/0000-0003-4483-3701
authors.initials: J
authors.lastname: Deelen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.|Department of Endocrinology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Ko Willems
authors.identifier: http://orcid.org/0000-0002-2172-7394
authors.initials: KW
authors.lastname: van Dijk
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Room 2B-29, 1081 BT Amsterdam, The Netherlands.|EMGO Institute for Health and Care Research, Van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Jouke-Jan
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: van Leeuwen
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere University, Kalevantie 4, Tampere 33014, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
authors.forename: Evelin
authors.initials: E
authors.lastname: Mihailov
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, PO Box 41 Mannerheimintie 172, Helsinki 00014, Finland.|Department of Psychological and Brain Sciences, Indiana University, 1101 E 10th Street, Bloomington, Indiana 47405, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rose
authors.affiliation: Department of Geriatrics and Gerontology, Leiden University Medical Center, Postzone C7-Q, PO Box 9600, 2300RC Leiden, The Netherlands.
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Department of Clinical Physiology, University of Tampere and Tampere, University Hospital, PO Box 2000, FIN-33521 Tampere, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.affiliation: National Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.|Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.|Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum 2, Tukholmankatu 8, Helsinki 00290, Finland.
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.affiliation: German Center for Cardiovascular Research (DZHK e.V.), Partner Site Hamburg/Lübeck/Kiel, Martinistraße 52, 20246 Hamburg, Germany.|University Heart Center Hamburg, Clinic of general and interventional Cardiology, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.affiliation: Biocenter Oulu, University of Oulu, PO Box 5000, FI-90014 Oulu, Finland.|Medical Research Center, Internal Medicine, Oulu University Hospital, University of Oulu, Aapistie 5A, Oulu FI-90220, Finland.
authors.forename: Markku J
authors.initials: MJ
authors.lastname: Savolainen
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Aswin
authors.initials: A
authors.lastname: Verhoeven
authors.affiliation: Department of Medicine, University of Turku and Turku University Hospital, PB 52, 20521 Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Viikari
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Room 2B-29, 1081 BT Amsterdam, The Netherlands.|EMGO Institute for Health and Care Research, Van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Room 2B-29, 1081 BT Amsterdam, The Netherlands.|EMGO Institute for Health and Care Research, Van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: National Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.|Department of General Practice and Primary Health Care, University of Helsinki, PL 20, Tukholmankatu 8B, Helsinki 00029, Finland.|Folkhälsan Research Centre, Helsingfors Universitet, PB 63, Helsinki 00014, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: National Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.affiliation: Biocenter Oulu, University of Oulu, PO Box 5000, FI-90014 Oulu, Finland.|Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK.|Center for Life Course and Systems Epidemiology, Faculty of Medicine, University of Oulu, PL 5000, 90014 Oulu, Finland.|Unit of Primary Care, Oulu University Hospital, P.O. Box 20, OYS, Oulu 90029, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum 2, Tukholmankatu 8, Helsinki 00290, Finland.|Department of Public Health, Hjelt Institute, University of Helsinki, PO Box 41 Mannerheimintie 172, Helsinki 00014, Finland.|Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, PO Box 30 (Mannerheimintie 166), Helsinki 00300, Finland.
authors.forename: Jaakko
authors.identifier: http://orcid.org/0000-0002-3716-2455
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 4-8, Turku 20521, Finland.|Department of Clinical Physiology, Turku University Hospital, Kiinamyllynkatu 4-8, Turku 20521, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Raitakari
authors.affiliation: National Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: National Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.|Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum 2, Tukholmankatu 8, Helsinki 00290, Finland.|Department of Public Health, Hjelt Institute, University of Helsinki, PO Box 41 Mannerheimintie 172, Helsinki 00014, Finland.|Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, Kuopio 70210, Finland.|Biocenter Oulu, University of Oulu, PO Box 5000, FI-90014 Oulu, Finland.|Oulu University Hospital, Kajaanintie 50, Oulu 90220, Finland.|Computational Medicine, School of Social and Community Medicine, University of Bristol, Senate House, Tyndall Avenue, Bristol, Bristol BS8 1TH, UK.|Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, Bristol BS8 1TH, UK.
authors.forename: Mika
authors.initials: M
authors.lastname: Ala-Korpela
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D017270:Lipoprotein(a) / Q000235:genetics*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D057182:Mendelian Randomization Analysis; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D014280:Triglycerides / Q000378:metabolism; D055815:Young Adult
chemical_list: D017270:Lipoprotein(a); D008079:Lipoproteins, VLDL; D014280:Triglycerides