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

J. Kettunen; A. Demirkan; P. Würtz; H.H.M. Draisma; T. Haller; R. Rawal; A.A.M. Vaarhorst; A.J. Kangas; L.P. Lyytikäinen; M. Pirinen; R. Pool; A.-P. Sarin; P. Soininen; T. Tukiainen; Q. Wang; M. Tiainen; T. Tynkkynen; N. Amin; T. Zeller; M. Beekman; J. Deelen; K. Willems van Dijk; T. Esko; J.J. Hottenga; E.M. van Leeuwen; T. Lehtimäki; E. Mihailov; R.J. Rose; A.J. de Craen; C. Gieger; M. Kähönen; M. Perola; S. Blankenberg; M.J. Savolainen; A. Verhoeven; J. Viikari; G. Willemsen; D.I. Boomsma; C.M. van Duijn; J. Eriksson; A. Jula; M.R. Järvelin; J. Kaprio; A. Metspalu; O. Raitakari; V. Salomaa; P.E. Slagboom; M. Waldenberger; S. Ripatti; M. Ala-Korpela

doi:10.1038/ncomms11122

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

J. Kettunen, A. Demirkan, P. Würtz, H.H.M. Draisma, T. Haller, R. Rawal, A.A.M. Vaarhorst, A.J. Kangas, L.P. Lyytikäinen, M. Pirinen, R. Pool, A.-P. Sarin, P. Soininen, T. Tukiainen, Q. Wang, M. Tiainen, T. Tynkkynen, N. Amin, T. Zeller, M. BeekmanJ. Deelen, K. Willems van Dijk, T. Esko, J.J. Hottenga, E.M. van Leeuwen, T. Lehtimäki, E. Mihailov, R.J. Rose, A.J. de Craen, C. Gieger, M. Kähönen, M. Perola, S. Blankenberg, M.J. Savolainen, A. Verhoeven, J. Viikari, G. Willemsen, D.I. Boomsma, C.M. van Duijn, J. Eriksson, A. Jula, M.R. Järvelin, J. Kaprio, A. Metspalu, O. Raitakari, V. Salomaa, P.E. Slagboom, M. Waldenberger, S. Ripatti, M. Ala-Korpela

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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 - 2016

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Kettunen, J., Demirkan, A., Würtz, P., Draisma, H. H. M., Haller, T., Rawal, R., Vaarhorst, A. A. M., 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{ec4670e0907c4528916e039a0a08e169,

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 = "J. Kettunen and A. Demirkan and P. W{\"u}rtz and H.H.M. Draisma and T. Haller and R. Rawal and A.A.M. Vaarhorst and A.J. Kangas and L.P. Lyytik{\"a}inen and M. Pirinen and R. Pool and A.-P. Sarin and P. Soininen and T. Tukiainen and Q. Wang and M. Tiainen and T. Tynkkynen and N. Amin and T. Zeller and M. Beekman and J. Deelen and {Willems van Dijk}, K. and T. Esko and J.J. Hottenga and {van Leeuwen}, E.M. and T. Lehtim{\"a}ki and E. Mihailov and R.J. Rose and {de Craen}, A.J. and C. Gieger and M. K{\"a}h{\"o}nen and M. Perola and S. Blankenberg and M.J. Savolainen and A. Verhoeven and J. Viikari and G. Willemsen and D.I. Boomsma and {van Duijn}, C.M. and J. Eriksson and A. Jula and M.R. J{\"a}rvelin and J. Kaprio and A. Metspalu and O. Raitakari and V. Salomaa and P.E. Slagboom and M. Waldenberger and S. Ripatti and M. Ala-Korpela",

year = "2016",

doi = "10.1038/ncomms11122",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Kettunen, J, Demirkan, A, Würtz, P, Draisma, HHM, Haller, T, Rawal, R, Vaarhorst, AAM, Kangas, AJ, Lyytikäinen, LP, Pirinen, M, Pool, R, Sarin, A-P, Soininen, P, Tukiainen, T, Wang, Q, Tiainen, M, Tynkkynen, T, Amin, N, Zeller, T, Beekman, M, Deelen, J, Willems van Dijk, K, Esko, T, Hottenga, JJ, van Leeuwen, EM, Lehtimäki, T, Mihailov, E, Rose, RJ, de Craen, AJ, 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, Slagboom, PE, 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, J.

AU - Demirkan, A.

AU - Würtz, P.

AU - Draisma, H.H.M.

AU - Haller, T.

AU - Rawal, R.

AU - Vaarhorst, A.A.M.

AU - Kangas, A.J.

AU - Lyytikäinen, L.P.

AU - Pirinen, M.

AU - Pool, R.

AU - Sarin, A.-P.

AU - Soininen, P.

AU - Tukiainen, T.

AU - Wang, Q.

AU - Tiainen, M.

AU - Tynkkynen, T.

AU - Amin, N.

AU - Zeller, T.

AU - Beekman, M.

AU - Deelen, J.

AU - Willems van Dijk, K.

AU - Esko, T.

AU - Hottenga, J.J.

AU - van Leeuwen, E.M.

AU - Lehtimäki, T.

AU - Mihailov, E.

AU - Rose, R.J.

AU - de Craen, A.J.

AU - Gieger, C.

AU - Kähönen, M.

AU - Perola, M.

AU - Blankenberg, S.

AU - Savolainen, M.J.

AU - Verhoeven, A.

AU - Viikari, J.

AU - Willemsen, G.

AU - Boomsma, D.I.

AU - van Duijn, C.M.

AU - Eriksson, J.

AU - Jula, A.

AU - Järvelin, M.R.

AU - Kaprio, J.

AU - Metspalu, A.

AU - Raitakari, O.

AU - Salomaa, V.

AU - Slagboom, P.E.

AU - Waldenberger, M.

AU - Ripatti, S.

AU - Ala-Korpela, M.

PY - 2016

Y1 - 2016

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.

U2 - 10.1038/ncomms11122

DO - 10.1038/ncomms11122

M3 - Article

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

Abstract

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