Genome-wide characterization of circulating metabolic biomarkers.

Autor: Karjalainen MK; Systems Epidemiology, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland. minna.k.karjalainen@oulu.fi.; Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland. minna.k.karjalainen@oulu.fi.; Northern Finland Birth Cohorts, Arctic Biobank, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, Finland. minna.k.karjalainen@oulu.fi., Karthikeyan S; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Oliver-Williams C; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Public Health Specialty Training Programme, Cambridge, UK., Sliz E; Systems Epidemiology, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.; Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland., Allara E; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK., Fung WT; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK., Surendran P; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Rutherford Fund Fellow, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK., Zhang W; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.; Department of Cardiology, Ealing Hospital, London North West University Healthcare NHS Trust, London, UK., Jousilahti P; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland., Kristiansson K; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland., Salomaa V; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland., Goodwin M; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK., Hughes DA; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK., Boehnke M; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA., Fernandes Silva L; Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland., Yin X; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.; Department of Epidemiology, School of Public Health, Nanjing Medical University, Jiangsu, China., Mahajan A; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.; Genentech, South San Francisco, CA, USA., Neville MJ; NIHR Oxford Biomedical Research Centre, OUHFT Oxford, Oxford, UK.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., van Zuydam NR; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., de Mutsert R; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands., Li-Gao R; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands., Mook-Kanamori DO; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands., Demirkan A; Surrey Institute for People-Centred AI, University of Surrey, Guildford, UK.; Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford, UK., Liu J; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands., Noordam R; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands., Trompet S; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands., Chen Z; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; MRC Population Health Research Unit, University of Oxford, Oxford, UK., Kartsonaki C; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; MRC Population Health Research Unit, University of Oxford, Oxford, UK., Li L; Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.; Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China.; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing, China., Lin K; Nuffield Department of Population Health, University of Oxford, Oxford, UK., Hagenbeek FA; Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Hottenga JJ; Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Amsterdam Public Health Research Institute, Amsterdam, The Netherlands., Pool R; Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Amsterdam Public Health Research Institute, Amsterdam, The Netherlands., Ikram MA; Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands., van Meurs J; Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands., Haller T; Institute of Genomics, University of Tartu, Tartu, Estonia., Milaneschi Y; Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Kähönen M; Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.; Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland., Mishra PP; Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.; Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland., Joshi PK; Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, Scotland., Macdonald-Dunlop E; Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, Scotland., Mangino M; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.; NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK., Zierer J; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK., Acar IE; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands., Hoyng CB; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands., Lechanteur YTE; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands., Franke L; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Kurilshikov A; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Zhernakova A; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Beekman M; Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands., van den Akker EB; Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.; Center for Computational Biology, Leiden University Medical Center, Leiden, The Netherlands.; The Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands., Kolcic I; Department of Public Health, School of Medicine, University of Split, Split, Croatia., Polasek O; Department of Public Health, School of Medicine, University of Split, Split, Croatia., Rudan I; Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, Scotland., Gieger C; Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany., Waldenberger M; Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany., Asselbergs FW; Amsterdam University Medical Centers, Department of Cardiology, University of Amsterdam, Amsterdam, The Netherlands.; Health Data Research UK and Institute of Health Informatics, University College London, London, UK., Hayward C; Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Fu J; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.; Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., den Hollander AI; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.; Genomics Research Center, Abbvie, Cambridge, MA, USA., Menni C; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK., Spector TD; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK., Wilson JF; Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, Scotland.; Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Lehtimäki T; Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.; Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland., Raitakari OT; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.; Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.; InFLAMES Research Flagship, University of Turku, Turku, Finland., Penninx BWJH; Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Esko T; Institute of Genomics, University of Tartu, Tartu, Estonia., Walters RG; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; MRC Population Health Research Unit, University of Oxford, Oxford, UK., Jukema JW; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.; Netherlands Heart Institute, Utrecht, The Netherlands., Sattar N; School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK., Ghanbari M; Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands., Willems van Dijk K; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.; Department of Internal Medicine, Division Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.; Leiden Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Karpe F; NIHR Oxford Biomedical Research Centre, OUHFT Oxford, Oxford, UK.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., McCarthy MI; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.; Genentech, South San Francisco, CA, USA., Laakso M; Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.; Kuopio University Hospital, Kuopio, Finland., Järvelin MR; Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland.; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK.; Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland., Timpson NJ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK., Perola M; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.; Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.; Estonian Genome Center, University of Tartu, Tartu, Estonia., Kooner JS; Department of Cardiology, Ealing Hospital, London North West University Healthcare NHS Trust, London, UK.; Imperial College Healthcare NHS Trust, Imperial College London, London, UK.; MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.; National Heart and Lung Institute, Imperial College London, London, UK., Chambers JC; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.; Department of Cardiology, Ealing Hospital, London North West University Healthcare NHS Trust, London, UK.; Imperial College Healthcare NHS Trust, Imperial College London, London, UK.; MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore., van Duijn C; Nuffield Department of Population Health, University of Oxford, Oxford, UK., Slagboom PE; Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands., Boomsma DI; Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.; Amsterdam Reproduction and Development (AR&D) Research Institute, Amsterdam, The Netherlands., Danesh J; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.; Department of Human Genetics, Wellcome Sanger Institute, Hinxton, UK., Ala-Korpela M; Systems Epidemiology, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.; Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland.; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Butterworth AS; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK., Kettunen J; Systems Epidemiology, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.; Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland.; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Apr; Vol. 628 (8006), pp. 130-138. Date of Electronic Publication: 2024 Mar 06.
DOI: 10.1038/s41586-024-07148-y
Abstrakt: Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism 1-7 . This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases 8-11 . 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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