Genome-wide characterization of circulating metabolic biomarkers

Minna K. Karjalainen (), Savita Karthikeyan, Clare Oliver-Williams, Eeva Sliz, Elias Allara, Wing Tung Fung, Praveen Surendran, Weihua Zhang, Pekka Jousilahti, Kati Kristiansson, Veikko Salomaa, Matt Goodwin, David A. Hughes, Michael Boehnke, Lilian Fernandes Silva, Xianyong Yin, Anubha Mahajan, Matt J. Neville, Natalie R. Zuydam, Renée Mutsert, Ruifang Li-Gao, Dennis O. Mook-Kanamori, Ayse Demirkan, Jun Liu, Raymond Noordam, Stella Trompet, Zhengming Chen, Christiana Kartsonaki, Liming Li, Kuang Lin, Fiona A. Hagenbeek, Jouke Jan Hottenga, René Pool, M. Arfan Ikram, Joyce Meurs, Toomas Haller, Yuri Milaneschi, Mika Kähönen, Pashupati P. Mishra, Peter K. Joshi, Erin Macdonald-Dunlop, Massimo Mangino, Jonas Zierer, Ilhan E. Acar, Carel B. Hoyng, Yara T. E. Lechanteur, Lude Franke, Alexander Kurilshikov, Alexandra Zhernakova, Marian Beekman, Erik B. Akker, Ivana Kolcic, Ozren Polasek, Igor Rudan, Christian Gieger, Melanie Waldenberger, Folkert W. Asselbergs, Caroline Hayward, Jingyuan Fu, Anneke I. Hollander, Cristina Menni, Tim D. Spector, James F. Wilson, Terho Lehtimäki, Olli T. Raitakari, Brenda W. J. H. Penninx, Tonu Esko, Robin G. Walters, J. Wouter Jukema, Naveed Sattar, Mohsen Ghanbari, Ko Willems van Dijk, Fredrik Karpe, Mark I. McCarthy, Markku Laakso, Marjo-Riitta Järvelin, Nicholas J. Timpson, Markus Perola, Jaspal S. Kooner, John C. Chambers, Cornelia Duijn, P. Eline Slagboom, Dorret I. Boomsma, John Danesh, Mika Ala-Korpela, Adam S. Butterworth and Johannes Kettunen
Additional contact information
Minna K. Karjalainen: University of Oulu and Biocenter Oulu
Savita Karthikeyan: University of Cambridge
Clare Oliver-Williams: University of Cambridge
Eeva Sliz: University of Oulu and Biocenter Oulu
Elias Allara: University of Cambridge
Wing Tung Fung: University of Cambridge
Praveen Surendran: University of Cambridge
Weihua Zhang: Imperial College London
Pekka Jousilahti: Finnish Institute for Health and Welfare
Kati Kristiansson: Finnish Institute for Health and Welfare
Veikko Salomaa: Finnish Institute for Health and Welfare
Matt Goodwin: University of Bristol
David A. Hughes: University of Bristol
Michael Boehnke: University of Michigan
Lilian Fernandes Silva: University of Eastern Finland
Xianyong Yin: University of Michigan
Anubha Mahajan: University of Oxford
Matt J. Neville: NIHR Oxford Biomedical Research Centre, OUHFT Oxford
Natalie R. Zuydam: University of Oxford
Renée Mutsert: Leiden University Medical Center
Ruifang Li-Gao: Leiden University Medical Center
Dennis O. Mook-Kanamori: Leiden University Medical Center
Ayse Demirkan: University of Surrey
Jun Liu: University of Oxford
Raymond Noordam: Leiden University Medical Center
Stella Trompet: Leiden University Medical Center
Zhengming Chen: University of Oxford
Christiana Kartsonaki: University of Oxford
Liming Li: Peking University
Kuang Lin: University of Oxford
Fiona A. Hagenbeek: Vrije Universiteit Amsterdam
Jouke Jan Hottenga: Vrije Universiteit Amsterdam
René Pool: Vrije Universiteit Amsterdam
M. Arfan Ikram: University Medical Center Rotterdam
Joyce Meurs: University Medical Center Rotterdam
Toomas Haller: University of Tartu
Yuri Milaneschi: Vrije Universiteit Amsterdam
Mika Kähönen: Tampere University
Pashupati P. Mishra: Tampere University
Peter K. Joshi: Usher Institute, University of Edinburgh
Erin Macdonald-Dunlop: Usher Institute, University of Edinburgh
Massimo Mangino: King’s College London
Jonas Zierer: King’s College London
Ilhan E. Acar: ETH Zurich
Carel B. Hoyng: Radboud University Medical Center
Yara T. E. Lechanteur: Radboud University Medical Center
Lude Franke: University Medical Center Groningen, University of Groningen
Alexander Kurilshikov: University Medical Center Groningen, University of Groningen
Alexandra Zhernakova: University Medical Center Groningen, University of Groningen
Marian Beekman: Leiden University Medical Center
Erik B. Akker: Leiden University Medical Center
Ivana Kolcic: University of Split
Ozren Polasek: University of Split
Igor Rudan: Usher Institute, University of Edinburgh
Christian Gieger: German Research Center for Environmental Health
Melanie Waldenberger: German Research Center for Environmental Health
Folkert W. Asselbergs: University of Amsterdam
Caroline Hayward: University of Edinburgh
Jingyuan Fu: University Medical Center Groningen, University of Groningen
Anneke I. Hollander: Radboud University Medical Center
Cristina Menni: King’s College London
Tim D. Spector: King’s College London
James F. Wilson: Usher Institute, University of Edinburgh
Terho Lehtimäki: Tampere University
Olli T. Raitakari: University of Turku
Brenda W. J. H. Penninx: Vrije Universiteit Amsterdam
Tonu Esko: University of Tartu
Robin G. Walters: University of Oxford
J. Wouter Jukema: Leiden University Medical Center
Naveed Sattar: University of Glasgow
Mohsen Ghanbari: University Medical Center Rotterdam
Ko Willems van Dijk: Leiden University Medical Center
Fredrik Karpe: NIHR Oxford Biomedical Research Centre, OUHFT Oxford
Mark I. McCarthy: University of Oxford
Markku Laakso: University of Eastern Finland
Marjo-Riitta Järvelin: University of Oulu
Nicholas J. Timpson: University of Bristol
Markus Perola: Finnish Institute for Health and Welfare
Jaspal S. Kooner: London North West University Healthcare NHS Trust
John C. Chambers: Imperial College London
Cornelia Duijn: University of Oxford
P. Eline Slagboom: Leiden University Medical Center
Dorret I. Boomsma: Vrije Universiteit Amsterdam
John Danesh: University of Cambridge
Mika Ala-Korpela: University of Oulu and Biocenter Oulu
Adam S. Butterworth: University of Cambridge
Johannes Kettunen: University of Oulu and Biocenter Oulu

Nature, 2024, vol. 628, issue 8006, 130-138

Abstract: Abstract Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1–7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8–11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

Date: 2024
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DOI: 10.1038/s41586-024-07148-y

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