Genome-wide characterization of circulating metabolic biomarkers

• 成果类型: Article
• 署名作者: 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, Renee; 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, Rene; Ikram, M. Arfan; van Meurs, Joyce; Haller, Toomas; Milaneschi, Yuri; Kahonen, 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.; Lehtimaki, 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; Jarvelin, Marjo-Riitta; Timpson, Nicholas J.; Perola, Markus; Kooner, Jaspal S.; Chambers, John C.; van Duijn, Cornelia; Slagboom, P. Eline; Boomsma, Dorret I.; Danesh, John; Ala-Korpela, Mika; Butterworth, Adam S.; Kettunen, Johannes
• 署名单位: University of Oulu; University of Oulu; University of Oulu; University of Oulu; University of Cambridge; University of Cambridge; University of Cambridge; University of Cambridge; University of Cambridge; University of Cambridge; Imperial College London; University of Bristol; University of Bristol; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Eastern Finland; Nanjing Medical University; University of Oxford; Wellcome Centre for Human Genetics; University of Oxford; University of Oxford; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; University of Surrey; University of Surrey; University of Oxford; Erasmus University Rotterdam; Erasmus MC; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); University of Oxford; Peking University; Peking University; Peking University; Vrije Universiteit Amsterdam; Vrije Universiteit Amsterdam; University of Helsinki; Erasmus University Rotterdam; Erasmus MC; University of Tartu; Vrije Universiteit Amsterdam; Vrije Universiteit Amsterdam; University of Amsterdam; Tampere University; Tampere University; Tampere University Hospital; Tampere University; University of Edinburgh; University of London; King's College London; Guy's & St Thomas' NHS Foundation Trust; Swiss Federal Institutes of Technology Domain; ETH Zurich; Radboud University Nijmegen; University of Groningen; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Delft University of Technology; University of Split; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Munich Heart Alliance; German Centre for Cardiovascular Research; University of Amsterdam; University of London; University College London; University of London; University College London; University of Edinburgh; University of Groningen; AbbVie; University of Turku; University of Turku; University of Turku; University of Turku; University of Turku; University of Glasgow; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; University of Eastern Finland; University of Eastern Finland Hospital; Kuopio University Hospital; Brunel University; University of Oulu; University of Helsinki; University of Tartu; Imperial College London; Imperial College London; Imperial College London; Nanyang Technological University; Wellcome Trust Sanger Institute; University of Eastern Finland; Roche Holding; Roche Holding USA; Genentech
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4308
• DOI: 10.1038/s41586-024-07148-y
• 发表日期: 2024-04-04
• 关键词: mendelian randomization; fatty-acids; genetic inhibition; aging research; ketone-bodies; association; loci; variants; heart; RISK

摘要

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. A meta-analysis of genome-wide association studies for 233 circulating metabolites from 33 cohorts reveals more than 400 loci and suggests probable causal genes, providing insights into metabolic pathways and disease aetiology.