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Get Free AccessGenome-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.
Johannes Kettunen, Ayşe Demirkan, Peter Würtz, Harmen H. M. Draisma, Toomas Haller, Rajesh Rawal, Anika A. M. 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, Jin‐Moo Lee, 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 G. Eriksson, Antti Jula, Paul M Ridker, Jaakko Kaprio, Andres Metspalu, Olli T. Raitakari, Veikko Salomaa, P. Eline Slagboom, Mélanie Waldenberger, Samuli Ripatti, Mika Ala‐Korpela (2016). Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. , 7(1), DOI: https://doi.org/10.1038/ncomms11122.
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Type
Article
Year
2016
Authors
50
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1038/ncomms11122
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