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Cited by 786Genetic Associations and EpidemiologyMetabolomics and Mass Spectrometry StudiesGenetic Mapping and Diversity in Plants and Animals

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

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Kettunen, Johannes, Demirkan, Ayşe, Würtz, Peter, Draisma, Harmen H.M., Haller, Toomas, Rawal, Rajesh, Vaarhorst, Anika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Pirinen, Matti, Pool, René, Sarin, Antti-Pekka, Soininen, Pasi, Tukiainen, Taru, Wang, Qin, Tiainen, Mika, Tynkkynen, Tuulia, Amin, Najaf, Zeller, Tanja, Beekman, Marian, Deelen, Joris, van Dijk, Ko Willems, Esko, Tõnu, Hottenga, Jouke-Jan, van Leeuwen, Elisabeth M, Lehtimäki, Terho, Mihailov, Evelin, Rose, Richard J., de Craen, Anton J.M., Gieger, Christian, Kähönen, Mika, Perola, Markus, Blankenberg, Stefan, Savolainen, Markku J., Verhoeven, Aswin, Viikari, Jorma, Willemsen, Gonneke, Boomsma, Dorret I., van Duijn, Cornelia M., Eriksson, Johan, Jula, Antti, Järvelin, Marjo-Riitta, Kaprio, Jaakko, Metspalu, Andres, Raitakari, Olli, Salomaa, Veikko, Slagboom, P. Eline, Waldenberger, Melanie, Ripatti, Samuli, Ala-Korpela, Mika·2016·Nature Communications
DOI 10.1038/ncomms11122PMC PMC4814583
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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.

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Figure 1 A genome-wide association study for circulating metabolites. Study was conducted to elucidate the genetic variation of systemic metabolism and to discover new metabolic associations in established loci. We also revealed an intriguing novel relation between Lp(a) and systemic triglyceride and VLDL metabolism. Thereby, we highlighted the LPA locus and generated the best possible Lp(a) genetic risk score (GRSLp(a)) that enabled us to clarify causal associations between Lp(a) and systemic triglyceride and lipoprotein metabolism. Further, with the aid of extensive electronic health-care records, we were able to use the GRSLp(a) to show that Lp(a) is associated with ischaemic heart disease but not strongly with other morbidities. Put together, these findings suggest safe molecular intervention on LPA to reduce individual cardiovascular risk.
Figure 1 A genome-wide association study for circulating metabolites. Study was conducted to elucidate the genetic variation of systemic metabolism and to discover new metabolic associations in established loci. We also revealed an intriguing novel relation between Lp(a) and systemic triglyceride and VLDL metabolism. Thereby, we highlighted the LPA locus and generated the best possible Lp(a) genetic risk score (GRSLp(a)) that enabled us to clarify causal associations between Lp(a) and systemic triglyceride and lipoprotein metabolism. Further, with the aid of extensive electronic health-care records, we were able to use the GRSLp(a) to show that Lp(a) is associated with ischaemic heart disease but not strongly with other morbidities. Put together, these findings suggest safe molecular intervention on LPA to reduce individual cardiovascular risk.CC BY · PubMed Central
Figure 2 The association pattern of the Lp(a) variant rs10455872 G-allele across all circulating metabolic traits. Each bar represents the association with respective metabolic trait, the size of the bar is the linear regression effect estimate, colouring refers to effect direction and significance is indicated with filled circles for P<2.27 × 10−9 and unfilled circles for P<5 × 10−8. Metabolite abbreviations and sample sizes are given in Supplementary Table 1, the strongest association was observed for the mean diameter of very-low-density lipoprotein particles (VLDL.D).
Figure 2 The association pattern of the Lp(a) variant rs10455872 G-allele across all circulating metabolic traits. Each bar represents the association with respective metabolic trait, the size of the bar is the linear regression effect estimate, colouring refers to effect direction and significance is indicated with filled circles for P<2.27 × 10−9 and unfilled circles for P<5 × 10−8. Metabolite abbreviations and sample sizes are given in Supplementary Table 1, the strongest association was observed for the mean diameter of very-low-density lipoprotein particles (VLDL.D).CC BY · PubMed Central
Figure 3 Evaluation of the causative role of the Lp(a) on the circulating metabolic measures via Mendelian randomization. Yellow linear regression estimates are observational associations, blue are GRSLp(a) estimates and red are the causal effect estimates. Those metabolic traits are listed for which the associations in the meta-analysis were significant with genome-wide threshold (P<2.3 × 10−9). Metabolite abbreviations are given in Supplementary Table 1.
Figure 3 Evaluation of the causative role of the Lp(a) on the circulating metabolic measures via Mendelian randomization. Yellow linear regression estimates are observational associations, blue are GRSLp(a) estimates and red are the causal effect estimates. Those metabolic traits are listed for which the associations in the meta-analysis were significant with genome-wide threshold (P<2.3 × 10−9). Metabolite abbreviations are given in Supplementary Table 1.CC BY · PubMed Central

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Authors
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., Beekman, M., Deelen, J., van Dijk, K. W., Esko, T., Hottenga, J.-J., van Leeuwen, E. M., Lehtimäki, T., Mihailov, E., Rose, R. J., de Craen, A. J. M., Gieger, C., Kähönen, M., Perola, M., Blankenberg, S., Savolainen, M. J., Verhoeven, A., Viikari, J., Willemsen, G., Boomsma, D. I., van Duijn, C. M., Eriksson, J., Jula, A., Järvelin, M.-R., Kaprio, J., Metspalu, A., Raitakari, O., Salomaa, V., Slagboom, P. E., Waldenberger, M., Ripatti, S., & Ala-Korpela, M.
Affiliations
  • University of Eastern Finland (FI)
  • Leiden University Medical Center (NL)
  • University of Oulu (FI)
  • Amsterdam Neuroscience (NL)
  • University of Tartu (EE)
  • Helmholtz Munich (DE)
  • Tampere University (FI)
  • University of Helsinki (FI)
  • Amsterdam Public Health (NL)
  • Harvard University (US)
  • Erasmus MC (NL)
  • Universität Hamburg (DE)
  • Tampere University Hospital (FI)
  • Oulu University Hospital (FI)
  • University of Turku (FI)
  • Finnish Institute for Health and Welfare (FI)
Corresponding author
Kettunen, Johannes
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-03-23
Volume
7
Issue
1
Pages
11122-11122
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms11122
PMC
PMC4814583
OpenAlex
W2310542696
Cited by
738
References
33
Citations by year
2026: 35 · 2025: 76 · 2024: 118 · 2023: 89 · 2022: 86 · 2021: 84 · 2020: 75 · 2019: 75 · 2018: 52 · 2017: 37 · 2016: 9
FWCI
46.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
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  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
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  • Tampere University Institutional Repository (Tampere University) (publishedVersion, cc-by)
  • Työväentutkimus Vuosikirja (submittedVersion, cc-by)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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  • Bristol Research (University of Bristol) (submittedVersion, cc-by)
  • VU Research Portal (submittedVersion, other-oa)
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  • Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
Novo Nordisk Fonden (NNF15OC0015998)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
circulating metabolites, lipoprotein(a), LPA gene, genetic loci, amino acids, pyruvate, fatty acids, triglyceride metabolism, lipoprotein metabolism, cardiovascular risk, pleiotropy, Mendelian randomization, genetic fine-mapping
MeSH terms
Adult, Aged, Cardiovascular Diseases, Chromosome Mapping, Female, Humans, Lipoproteins, VLDL, Male, Middle Aged, Magnetic Resonance Spectroscopy, Triglycerides, Lipoprotein(a), Genetic Predisposition to Disease, Genome-Wide Association Study, Metabolomics, Young Adult, Mendelian Randomization Analysis

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