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

Johannes Kettunen; Ayse 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; Mika Ala-Korpela

doi:10.1038/ncomms11122

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

Johannes Kettunen^*
, Ayse 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, Mika Ala-Korpela

^*Corresponding author for this work

University of Oulu
National Institute for Health and Welfare
University of Eastern Finland
Leiden University
Erasmus University Rotterdam
Vrije Universiteit Amsterdam
University of Amsterdam
Neuroscience Campus Amsterdam
University of Tartu
Helmholtz Zentrum München - German Research Center for Environmental Health
Fimlab Laboratories
University of Helsinki
Massachusetts General Hospital
Broad Institute
Harvard University
German Centre for Cardiovascular Research
University of Hamburg
Indiana University Bloomington
Tampere University
University of Turku
Imperial College London
Wellcome Trust Sanger Institute
University of Bristol

Research output: Contribution to journal › Article › peer-review

576 Citations (Scopus)

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.

Original language	English
Article number	11122
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11122
Publication status	Published - 23 Mar 2016
Externally published	Yes

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10.1038/ncomms11122

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Kettunen, J., Demirkan, A., Würtz, P., Draisma, H. H. M., Haller, T., Rawal, R., Vaarhorst, A., Kangas, A. J., Lyytikäinen, L. P., Pirinen, M., Pool, R., Sarin, A. P., Soininen, P., Tukiainen, T., Wang, Q., Tiainen, M., Tynkkynen, T., Amin, N., Zeller, T., ... Ala-Korpela, M. (2016). Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. Nature Communications, 7, Article 11122. https://doi.org/10.1038/ncomms11122

@article{7700886bf91b4bc497287af3098103b7,

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.",

author = "Johannes Kettunen and Ayse Demirkan and Peter W{\"u}rtz and Draisma, \{Harmen H.M.\} and Toomas Haller and Rajesh Rawal and Anika Vaarhorst and Kangas, \{Antti J.\} and Lyytik{\"a}inen, \{Leo Pekka\} and Matti Pirinen and Ren{\'e} Pool and Sarin, \{Antti Pekka\} and Pasi Soininen and Taru Tukiainen and Qin Wang and Mika Tiainen and Tuulia Tynkkynen and Najaf Amin and Tanja Zeller and Marian Beekman and Joris Deelen and \{Van Dijk\}, \{Ko Willems\} and T{\~o}nu Esko and Hottenga, \{Jouke Jan\} and \{Van Leeuwen\}, \{Elisabeth M.\} and Terho Lehtim{\"a}ki and Evelin Mihailov and Rose, \{Richard J.\} and \{De Craen\}, \{Anton J.M.\} and Christian Gieger and Mika K{\"a}h{\"o}nen and Markus Perola and Stefan Blankenberg and Savolainen, \{Markku J.\} and Aswin Verhoeven and Jorma Viikari and Gonneke Willemsen and Boomsma, \{Dorret I.\} and \{Van Duijn\}, \{Cornelia M.\} and Johan Eriksson and Antti Jula and J{\"a}rvelin, \{Marjo Riitta\} and Jaakko Kaprio and Andres Metspalu and Olli Raitakari and Veikko Salomaa and \{Eline Slagboom\}, P. and Melanie Waldenberger and Samuli Ripatti and Mika Ala-Korpela",

year = "2016",

month = mar,

day = "23",

doi = "10.1038/ncomms11122",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Kettunen, J, Demirkan, A, Würtz, P, Draisma, HHM, Haller, T, Rawal, R, Vaarhorst, A, Kangas, AJ, Lyytikäinen, LP, Pirinen, M, Pool, R, Sarin, AP, Soininen, P, Tukiainen, T, Wang, Q, Tiainen, M, Tynkkynen, T, Amin, N, Zeller, T, Beekman, M, Deelen, J, Van Dijk, KW, Esko, T, Hottenga, JJ, Van Leeuwen, EM, Lehtimäki, T, Mihailov, E, Rose, RJ, De Craen, AJM, Gieger, C, Kähönen, M, Perola, M, Blankenberg, S, Savolainen, MJ, Verhoeven, A, Viikari, J, Willemsen, G, Boomsma, DI, Van Duijn, CM, Eriksson, J, Jula, A, Järvelin, MR, Kaprio, J, Metspalu, A, Raitakari, O, Salomaa, V, Eline Slagboom, P, Waldenberger, M, Ripatti, S & Ala-Korpela, M 2016, 'Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA', Nature Communications, vol. 7, 11122. https://doi.org/10.1038/ncomms11122

TY - JOUR

T1 - Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

AU - Kettunen, Johannes

AU - Demirkan, Ayse

AU - Würtz, Peter

AU - Draisma, Harmen H.M.

AU - Haller, Toomas

AU - Rawal, Rajesh

AU - Vaarhorst, Anika

AU - Kangas, Antti J.

AU - Lyytikäinen, Leo Pekka

AU - Pirinen, Matti

AU - Pool, René

AU - Sarin, Antti Pekka

AU - Soininen, Pasi

AU - Tukiainen, Taru

AU - Wang, Qin

AU - Tiainen, Mika

AU - Tynkkynen, Tuulia

AU - Amin, Najaf

AU - Zeller, Tanja

AU - Beekman, Marian

AU - Deelen, Joris

AU - Van Dijk, Ko Willems

AU - Esko, Tõnu

AU - Hottenga, Jouke Jan

AU - Van Leeuwen, Elisabeth M.

AU - Lehtimäki, Terho

AU - Mihailov, Evelin

AU - Rose, Richard J.

AU - De Craen, Anton J.M.

AU - Gieger, Christian

AU - Kähönen, Mika

AU - Perola, Markus

AU - Blankenberg, Stefan

AU - Savolainen, Markku J.

AU - Verhoeven, Aswin

AU - Viikari, Jorma

AU - Willemsen, Gonneke

AU - Boomsma, Dorret I.

AU - Van Duijn, Cornelia M.

AU - Eriksson, Johan

AU - Jula, Antti

AU - Järvelin, Marjo Riitta

AU - Kaprio, Jaakko

AU - Metspalu, Andres

AU - Raitakari, Olli

AU - Salomaa, Veikko

AU - Eline Slagboom, P.

AU - Waldenberger, Melanie

AU - Ripatti, Samuli

AU - Ala-Korpela, Mika

PY - 2016/3/23

Y1 - 2016/3/23

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84962271039

U2 - 10.1038/ncomms11122

DO - 10.1038/ncomms11122

M3 - Article

C2 - 27005778

AN - SCOPUS:84962271039

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11122

ER -

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

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