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Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA
Open accessAbstract
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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“To also provide the more conservative results accounting for the number of tested proteins, we used a strategy described by Gao et al.35 and Kettunen et al.36, which accommodates the correlation between protein levels.”
From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as Kettunen et al. [36]
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“an MR study of body mass index (BMI) effects on type II diabetes yielded the same predicted relative risk reduction for a given difference in BMI among groups at different level of risk 148 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [148]
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Metadata
- 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
- Kettunen, Johannes
- Demirkan, Ayşe
- Würtz, Peter
- Draisma, Harmen H.M.
- Haller, Toomas
- Rawal, Rajesh
- Kangas, Antti J.
- Lyytikäinen, Leo-Pekka
- Pirinen, Matti
- Pool, René
- Sarin, Antti-Pekka
- 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
- Lehtimäki, Terho
- Rose, Richard J.
- Gieger, Christian
- Kähönen, Mika
- Perola, Markus
- Blankenberg, Stefan
- Savolainen, Markku J.
- Verhoeven, Aswin
- Viikari, Jorma
- Willemsen, Gonneke
- Boomsma, Dorret I.
- Eriksson, Johan
- Jula, Antti
- Järvelin, Marjo-Riitta
- Kaprio, Jaakko
- Metspalu, Andres
- Raitakari, Olli
- Salomaa, Veikko
- Slagboom, P. Eline
- Ripatti, Samuli
- Venue
- Nature Communications
- Published
- 2016-03-23
- Volume
- 7
- Issue
- 1
- Pages
- 11122-11122
- ISSN
- 2041-1723 (ISSN-L)
- 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
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by)
- 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)
- Site cant be reached (submittedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- VU Research Portal (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- 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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