Genome-wide characterization of circulating metabolic biomarkers

Karjalainen, Minna K. and Karthikeyan, Savita and Oliver-Williams, Clare and Sliz, Eeva and Allara, Elias and Fung, Wing Tung and Surendran, Praveen and Zhang, Weihua and Jousilahti, Pekka and Kristiansson, Kati and Salomaa, Veikko and Goodwin, Matt and Hughes, David A. and Boehnke, Michael and Fernandes Silva, Lilian and Yin, Xianyong and Mahajan, Anubha and Neville, Matt J. and van Zuydam, Natalie R. and de Mutsert, Renée and Li-Gao, Ruifang and Mook-Kanamori, Dennis O. and Demirkan, Ayse and Liu, Jun and Noordam, Raymond and Trompet, Stella and Chen, Zhengming and Kartsonaki, Christiana and Li, Liming and Lin, Kuang and Hagenbeek, Fiona A. and Hottenga, Jouke Jan and Pool, René and Ikram, M. Arfan and van Meurs, Joyce and Haller, Toomas and Milaneschi, Yuri and Kähönen, Mika and Mishra, Pashupati P. and Joshi, Peter K. and Macdonald-Dunlop, Erin and Mangino, Massimo and Zierer, Jonas and Acar, Ilhan E. and Hoyng, Carel B. and Lechanteur, Yara T. E. and Franke, Lude and Kurilshikov, Alexander and Zhernakova, Alexandra and Beekman, Marian and van den Akker, Erik B. and Kolcic, Ivana and Polasek, Ozren and Rudan, Igor and Gieger, Christian and Waldenberger, Melanie and Asselbergs, Folkert W. and Hayward, Caroline and Fu, Jingyuan and den Hollander, Anneke I. and Menni, Cristina and Spector, Tim D. and Wilson, James F. and Lehtimäki, Terho and Raitakari, Olli T. and Penninx, Brenda W. J. H. and Esko, Tonu and Walters, Robin G. and Jukema, J. Wouter and Sattar, Naveed and Ghanbari, Mohsen and Willems van Dijk, Ko and Karpe, Fredrik and McCarthy, Mark I. and Laakso, Markku and Järvelin, Marjo-Riitta and Timpson, Nicholas J. and Perola, Markus and Kooner, Jaspal S. and Chambers, John C. and van Duijn, Cornelia and Slagboom, P. Eline and Boomsma, Dorret I. and Danesh, John and Ala-Korpela, Mika and Butterworth, Adam S. and Kettunen, Johannes (2024) Genome-wide characterization of circulating metabolic biomarkers. Nature. ISSN 0028-0836

[thumbnail of s41586-024-07148-y.pdf] Text
s41586-024-07148-y.pdf - Published Version
Download (5MB)

Abstract

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8,9,10,11. 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.

Item Type: Article
Subjects: Science Global Plos > Multidisciplinary
Depositing User: Unnamed user with email support@science.globalplos.com
Date Deposited: 11 Mar 2024 10:23
Last Modified: 11 Mar 2024 10:23
URI: http://ebooks.manu2sent.com/id/eprint/2535

Actions (login required)

View Item
View Item