Genome-wide characterization of circulating metabolic biomarkers
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 mecha...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2024
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/179949 |
| _version_ | 1826112865850884096 |
|---|---|
| author | Karjalainen, Minna K. Karthikeyan, Savita Oliver-Williams, Clare Sliz, Eeva Allara, Elias Fung, Wing Tung Surendran, Praveen Zhang, Weihua Jousilahti, Pekka Kristiansson, Kati Salomaa, Veikko Goodwin, Matt Hughes, David A. Boehnke, Michael Silva, Lilian Fernandes Yin, Xianyong Mahajan, Anubha Neville, Matt J. van Zuydam, Natalie R. de Mutsert, Renée Li-Gao, Ruifang Mook-Kanamori, Dennis O. Demirkan, Ayse Liu, Jun Noordam, Raymond Trompet, Stella Chen, Zhengming Kartsonaki, Christiana Li, Liming Lin, Kuang Hagenbeek, Fiona A. Hottenga, Jouke Jan Pool, René Ikram, M. Arfan van Meurs, Joyce Haller, Toomas Milaneschi, Yuri Kähönen, Mika Mishra, Pashupati P. Joshi, Peter K. Macdonald-Dunlop, Erin Mangino, Massimo Zierer, Jonas Acar, Ilhan E. Hoyng, Carel B. Lechanteur, Yara T. E. Franke, Lude Kurilshikov, Alexander Zhernakova, Alexandra Beekman, Marian van den Akker, Erik B. Kolcic, Ivana Polasek, Ozren Rudan, Igor Gieger, Christian Waldenberger, Melanie Asselbergs, Folkert W. Hayward, Caroline Fu, Jingyuan den Hollander, Anneke I. Menni, Cristina Spector, Tim D. Wilson, James F. Lehtimäki, Terho Raitakari, Olli T. Penninx, Brenda W. J. H. Esko, Tonu Walters, Robin G. Jukema, J. Wouter Sattar, Naveed Ghanbari, Mohsen van Dijk, Ko Willems Karpe, Fredrik McCarthy, Mark I. Laakso, Markku Järvelin, Marjo-Riitta Timpson, Nicholas J. Perola, Markus Kooner, Jaspal S. Chambers, John Campbell van Duijn, Cornelia Slagboom, P. Eline Boomsma, Dorret I. Danesh, John Ala-Korpela, Mika Butterworth, Adam S. Kettunen, Johannes |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Karjalainen, Minna K. Karthikeyan, Savita Oliver-Williams, Clare Sliz, Eeva Allara, Elias Fung, Wing Tung Surendran, Praveen Zhang, Weihua Jousilahti, Pekka Kristiansson, Kati Salomaa, Veikko Goodwin, Matt Hughes, David A. Boehnke, Michael Silva, Lilian Fernandes Yin, Xianyong Mahajan, Anubha Neville, Matt J. van Zuydam, Natalie R. de Mutsert, Renée Li-Gao, Ruifang Mook-Kanamori, Dennis O. Demirkan, Ayse Liu, Jun Noordam, Raymond Trompet, Stella Chen, Zhengming Kartsonaki, Christiana Li, Liming Lin, Kuang Hagenbeek, Fiona A. Hottenga, Jouke Jan Pool, René Ikram, M. Arfan van Meurs, Joyce Haller, Toomas Milaneschi, Yuri Kähönen, Mika Mishra, Pashupati P. Joshi, Peter K. Macdonald-Dunlop, Erin Mangino, Massimo Zierer, Jonas Acar, Ilhan E. Hoyng, Carel B. Lechanteur, Yara T. E. Franke, Lude Kurilshikov, Alexander Zhernakova, Alexandra Beekman, Marian van den Akker, Erik B. Kolcic, Ivana Polasek, Ozren Rudan, Igor Gieger, Christian Waldenberger, Melanie Asselbergs, Folkert W. Hayward, Caroline Fu, Jingyuan den Hollander, Anneke I. Menni, Cristina Spector, Tim D. Wilson, James F. Lehtimäki, Terho Raitakari, Olli T. Penninx, Brenda W. J. H. Esko, Tonu Walters, Robin G. Jukema, J. Wouter Sattar, Naveed Ghanbari, Mohsen van Dijk, Ko Willems Karpe, Fredrik McCarthy, Mark I. Laakso, Markku Järvelin, Marjo-Riitta Timpson, Nicholas J. Perola, Markus Kooner, Jaspal S. Chambers, John Campbell van Duijn, Cornelia Slagboom, P. Eline Boomsma, Dorret I. Danesh, John Ala-Korpela, Mika Butterworth, Adam S. Kettunen, Johannes |
| author_sort | Karjalainen, Minna K. |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T03:13:47Z |
| format | Journal Article |
| id | ntu-10356/179949 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:13:47Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1799492024-09-08T15:38:04Z Genome-wide characterization of circulating metabolic biomarkers Karjalainen, Minna K. Karthikeyan, Savita Oliver-Williams, Clare Sliz, Eeva Allara, Elias Fung, Wing Tung Surendran, Praveen Zhang, Weihua Jousilahti, Pekka Kristiansson, Kati Salomaa, Veikko Goodwin, Matt Hughes, David A. Boehnke, Michael Silva, Lilian Fernandes Yin, Xianyong Mahajan, Anubha Neville, Matt J. van Zuydam, Natalie R. de Mutsert, Renée Li-Gao, Ruifang Mook-Kanamori, Dennis O. Demirkan, Ayse Liu, Jun Noordam, Raymond Trompet, Stella Chen, Zhengming Kartsonaki, Christiana Li, Liming Lin, Kuang Hagenbeek, Fiona A. Hottenga, Jouke Jan Pool, René Ikram, M. Arfan van Meurs, Joyce Haller, Toomas Milaneschi, Yuri Kähönen, Mika Mishra, Pashupati P. Joshi, Peter K. Macdonald-Dunlop, Erin Mangino, Massimo Zierer, Jonas Acar, Ilhan E. Hoyng, Carel B. Lechanteur, Yara T. E. Franke, Lude Kurilshikov, Alexander Zhernakova, Alexandra Beekman, Marian van den Akker, Erik B. Kolcic, Ivana Polasek, Ozren Rudan, Igor Gieger, Christian Waldenberger, Melanie Asselbergs, Folkert W. Hayward, Caroline Fu, Jingyuan den Hollander, Anneke I. Menni, Cristina Spector, Tim D. Wilson, James F. Lehtimäki, Terho Raitakari, Olli T. Penninx, Brenda W. J. H. Esko, Tonu Walters, Robin G. Jukema, J. Wouter Sattar, Naveed Ghanbari, Mohsen van Dijk, Ko Willems Karpe, Fredrik McCarthy, Mark I. Laakso, Markku Järvelin, Marjo-Riitta Timpson, Nicholas J. Perola, Markus Kooner, Jaspal S. Chambers, John Campbell van Duijn, Cornelia Slagboom, P. Eline Boomsma, Dorret I. Danesh, John Ala-Korpela, Mika Butterworth, Adam S. Kettunen, Johannes Lee Kong Chian School of Medicine (LKCMedicine) Medicine, Health and Life Sciences Genome-wide association study Metabolic fingerprinting 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. Ministry of Health (MOH) National Medical Research Council (NMRC) Published version The online version contains supplementary material available at https://doi.org/10.1038/s41586-024-07148-y. Please see the Supplementary Notes for acknowledgements and funding. 2024-09-04T06:21:20Z 2024-09-04T06:21:20Z 2024 Journal Article Karjalainen, M. K., Karthikeyan, S., Oliver-Williams, C., Sliz, E., Allara, E., Fung, W. T., Surendran, P., Zhang, W., Jousilahti, P., Kristiansson, K., Salomaa, V., Goodwin, M., Hughes, D. A., Boehnke, M., Silva, L. F., Yin, X., Mahajan, A., Neville, M. J., van Zuydam, N. R., ...Kettunen, J. (2024). Genome-wide characterization of circulating metabolic biomarkers. Nature, 628(8006), 130-138. https://dx.doi.org/10.1038/s41586-024-07148-y 0028-0836 https://hdl.handle.net/10356/179949 10.1038/s41586-024-07148-y 38448586 2-s2.0-85186912669 8006 628 130 138 en NMRC/STaR/0028/2017 Nature © 2024 The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Genome-wide association study Metabolic fingerprinting Karjalainen, Minna K. Karthikeyan, Savita Oliver-Williams, Clare Sliz, Eeva Allara, Elias Fung, Wing Tung Surendran, Praveen Zhang, Weihua Jousilahti, Pekka Kristiansson, Kati Salomaa, Veikko Goodwin, Matt Hughes, David A. Boehnke, Michael Silva, Lilian Fernandes Yin, Xianyong Mahajan, Anubha Neville, Matt J. van Zuydam, Natalie R. de Mutsert, Renée Li-Gao, Ruifang Mook-Kanamori, Dennis O. Demirkan, Ayse Liu, Jun Noordam, Raymond Trompet, Stella Chen, Zhengming Kartsonaki, Christiana Li, Liming Lin, Kuang Hagenbeek, Fiona A. Hottenga, Jouke Jan Pool, René Ikram, M. Arfan van Meurs, Joyce Haller, Toomas Milaneschi, Yuri Kähönen, Mika Mishra, Pashupati P. Joshi, Peter K. Macdonald-Dunlop, Erin Mangino, Massimo Zierer, Jonas Acar, Ilhan E. Hoyng, Carel B. Lechanteur, Yara T. E. Franke, Lude Kurilshikov, Alexander Zhernakova, Alexandra Beekman, Marian van den Akker, Erik B. Kolcic, Ivana Polasek, Ozren Rudan, Igor Gieger, Christian Waldenberger, Melanie Asselbergs, Folkert W. Hayward, Caroline Fu, Jingyuan den Hollander, Anneke I. Menni, Cristina Spector, Tim D. Wilson, James F. Lehtimäki, Terho Raitakari, Olli T. Penninx, Brenda W. J. H. Esko, Tonu Walters, Robin G. Jukema, J. Wouter Sattar, Naveed Ghanbari, Mohsen van Dijk, Ko Willems Karpe, Fredrik McCarthy, Mark I. Laakso, Markku Järvelin, Marjo-Riitta Timpson, Nicholas J. Perola, Markus Kooner, Jaspal S. Chambers, John Campbell van Duijn, Cornelia Slagboom, P. Eline Boomsma, Dorret I. Danesh, John Ala-Korpela, Mika Butterworth, Adam S. Kettunen, Johannes Genome-wide characterization of circulating metabolic biomarkers |
| title | Genome-wide characterization of circulating metabolic biomarkers |
| title_full | Genome-wide characterization of circulating metabolic biomarkers |
| title_fullStr | Genome-wide characterization of circulating metabolic biomarkers |
| title_full_unstemmed | Genome-wide characterization of circulating metabolic biomarkers |
| title_short | Genome-wide characterization of circulating metabolic biomarkers |
| title_sort | genome wide characterization of circulating metabolic biomarkers |
| topic | Medicine, Health and Life Sciences Genome-wide association study Metabolic fingerprinting |
| url | https://hdl.handle.net/10356/179949 |
| work_keys_str_mv | AT karjalainenminnak genomewidecharacterizationofcirculatingmetabolicbiomarkers AT karthikeyansavita genomewidecharacterizationofcirculatingmetabolicbiomarkers AT oliverwilliamsclare genomewidecharacterizationofcirculatingmetabolicbiomarkers AT slizeeva genomewidecharacterizationofcirculatingmetabolicbiomarkers AT allaraelias genomewidecharacterizationofcirculatingmetabolicbiomarkers AT fungwingtung genomewidecharacterizationofcirculatingmetabolicbiomarkers AT surendranpraveen genomewidecharacterizationofcirculatingmetabolicbiomarkers AT zhangweihua genomewidecharacterizationofcirculatingmetabolicbiomarkers AT jousilahtipekka genomewidecharacterizationofcirculatingmetabolicbiomarkers AT kristianssonkati genomewidecharacterizationofcirculatingmetabolicbiomarkers AT salomaaveikko genomewidecharacterizationofcirculatingmetabolicbiomarkers AT goodwinmatt genomewidecharacterizationofcirculatingmetabolicbiomarkers AT hughesdavida genomewidecharacterizationofcirculatingmetabolicbiomarkers AT boehnkemichael genomewidecharacterizationofcirculatingmetabolicbiomarkers AT silvalilianfernandes genomewidecharacterizationofcirculatingmetabolicbiomarkers AT yinxianyong genomewidecharacterizationofcirculatingmetabolicbiomarkers AT mahajananubha genomewidecharacterizationofcirculatingmetabolicbiomarkers AT nevillemattj genomewidecharacterizationofcirculatingmetabolicbiomarkers AT vanzuydamnatalier genomewidecharacterizationofcirculatingmetabolicbiomarkers AT demutsertrenee genomewidecharacterizationofcirculatingmetabolicbiomarkers AT ligaoruifang genomewidecharacterizationofcirculatingmetabolicbiomarkers AT mookkanamoridenniso genomewidecharacterizationofcirculatingmetabolicbiomarkers AT demirkanayse genomewidecharacterizationofcirculatingmetabolicbiomarkers AT liujun genomewidecharacterizationofcirculatingmetabolicbiomarkers AT noordamraymond genomewidecharacterizationofcirculatingmetabolicbiomarkers AT trompetstella genomewidecharacterizationofcirculatingmetabolicbiomarkers AT chenzhengming genomewidecharacterizationofcirculatingmetabolicbiomarkers AT kartsonakichristiana genomewidecharacterizationofcirculatingmetabolicbiomarkers AT liliming genomewidecharacterizationofcirculatingmetabolicbiomarkers AT linkuang genomewidecharacterizationofcirculatingmetabolicbiomarkers AT hagenbeekfionaa genomewidecharacterizationofcirculatingmetabolicbiomarkers AT hottengajoukejan genomewidecharacterizationofcirculatingmetabolicbiomarkers AT poolrene genomewidecharacterizationofcirculatingmetabolicbiomarkers AT ikrammarfan genomewidecharacterizationofcirculatingmetabolicbiomarkers AT vanmeursjoyce genomewidecharacterizationofcirculatingmetabolicbiomarkers AT hallertoomas genomewidecharacterizationofcirculatingmetabolicbiomarkers AT milaneschiyuri genomewidecharacterizationofcirculatingmetabolicbiomarkers AT kahonenmika genomewidecharacterizationofcirculatingmetabolicbiomarkers AT mishrapashupatip genomewidecharacterizationofcirculatingmetabolicbiomarkers AT joshipeterk genomewidecharacterizationofcirculatingmetabolicbiomarkers AT macdonalddunloperin genomewidecharacterizationofcirculatingmetabolicbiomarkers AT manginomassimo genomewidecharacterizationofcirculatingmetabolicbiomarkers AT ziererjonas genomewidecharacterizationofcirculatingmetabolicbiomarkers AT acarilhane genomewidecharacterizationofcirculatingmetabolicbiomarkers AT hoyngcarelb genomewidecharacterizationofcirculatingmetabolicbiomarkers AT lechanteuryarate genomewidecharacterizationofcirculatingmetabolicbiomarkers AT frankelude genomewidecharacterizationofcirculatingmetabolicbiomarkers AT kurilshikovalexander genomewidecharacterizationofcirculatingmetabolicbiomarkers AT zhernakovaalexandra genomewidecharacterizationofcirculatingmetabolicbiomarkers AT beekmanmarian genomewidecharacterizationofcirculatingmetabolicbiomarkers AT vandenakkererikb genomewidecharacterizationofcirculatingmetabolicbiomarkers AT kolcicivana genomewidecharacterizationofcirculatingmetabolicbiomarkers AT polasekozren genomewidecharacterizationofcirculatingmetabolicbiomarkers AT rudanigor genomewidecharacterizationofcirculatingmetabolicbiomarkers AT giegerchristian genomewidecharacterizationofcirculatingmetabolicbiomarkers AT waldenbergermelanie genomewidecharacterizationofcirculatingmetabolicbiomarkers AT asselbergsfolkertw genomewidecharacterizationofcirculatingmetabolicbiomarkers AT haywardcaroline genomewidecharacterizationofcirculatingmetabolicbiomarkers AT fujingyuan genomewidecharacterizationofcirculatingmetabolicbiomarkers AT denhollanderannekei genomewidecharacterizationofcirculatingmetabolicbiomarkers AT mennicristina genomewidecharacterizationofcirculatingmetabolicbiomarkers AT spectortimd genomewidecharacterizationofcirculatingmetabolicbiomarkers AT wilsonjamesf genomewidecharacterizationofcirculatingmetabolicbiomarkers AT lehtimakiterho genomewidecharacterizationofcirculatingmetabolicbiomarkers AT raitakariollit genomewidecharacterizationofcirculatingmetabolicbiomarkers AT penninxbrendawjh genomewidecharacterizationofcirculatingmetabolicbiomarkers AT eskotonu genomewidecharacterizationofcirculatingmetabolicbiomarkers AT waltersrobing genomewidecharacterizationofcirculatingmetabolicbiomarkers AT jukemajwouter genomewidecharacterizationofcirculatingmetabolicbiomarkers AT sattarnaveed genomewidecharacterizationofcirculatingmetabolicbiomarkers AT ghanbarimohsen genomewidecharacterizationofcirculatingmetabolicbiomarkers AT vandijkkowillems genomewidecharacterizationofcirculatingmetabolicbiomarkers AT karpefredrik genomewidecharacterizationofcirculatingmetabolicbiomarkers AT mccarthymarki genomewidecharacterizationofcirculatingmetabolicbiomarkers AT laaksomarkku genomewidecharacterizationofcirculatingmetabolicbiomarkers AT jarvelinmarjoriitta genomewidecharacterizationofcirculatingmetabolicbiomarkers AT timpsonnicholasj genomewidecharacterizationofcirculatingmetabolicbiomarkers AT perolamarkus genomewidecharacterizationofcirculatingmetabolicbiomarkers AT koonerjaspals genomewidecharacterizationofcirculatingmetabolicbiomarkers AT chambersjohncampbell genomewidecharacterizationofcirculatingmetabolicbiomarkers AT vanduijncornelia genomewidecharacterizationofcirculatingmetabolicbiomarkers AT slagboompeline genomewidecharacterizationofcirculatingmetabolicbiomarkers AT boomsmadorreti genomewidecharacterizationofcirculatingmetabolicbiomarkers AT daneshjohn genomewidecharacterizationofcirculatingmetabolicbiomarkers AT alakorpelamika genomewidecharacterizationofcirculatingmetabolicbiomarkers AT butterworthadams genomewidecharacterizationofcirculatingmetabolicbiomarkers AT kettunenjohannes genomewidecharacterizationofcirculatingmetabolicbiomarkers |