Rare and common genetic determinants of metabolic individuality and their effects on human health.

Autor: Surendran P; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Hinxton, UK.; Rutherford Fund Fellow, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Stewart ID; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Au Yeung VPW; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Pietzner M; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.; Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany., Raffler J; Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.; Digital Medicine, University Hospital of Augsburg, Augsburg, Germany., Wörheide MA; Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany., Li C; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Smith RF; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Wittemans LBL; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.; Big Data Institute, University of Oxford, Oxford, UK.; Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK., Bomba L; Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.; Open Targets, Wellcome Genome Campus, Hinxton, UK., Menni C; Department of Twin Research & Genetic Epidemiology, King's College London, London, UK., Zierer J; Department of Twin Research & Genetic Epidemiology, King's College London, London, UK., Rossi N; Department of Twin Research & Genetic Epidemiology, King's College London, London, UK., Sheridan PA; Metabolon, Morrisville, NC, USA., Watkins NA; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK., Mangino M; Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.; NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK., Hysi PG; Department of Twin Research & Genetic Epidemiology, King's College London, London, UK., Di Angelantonio E; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Hinxton, UK.; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.; Health Data Science Research Centre, Human Technopole, Milan, Italy., Falchi M; Department of Twin Research & Genetic Epidemiology, King's College London, London, UK., Spector TD; Department of Twin Research & Genetic Epidemiology, King's College London, London, UK., Soranzo N; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.; Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.; Open Targets, Wellcome Genome Campus, Hinxton, UK.; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.; Department of Haematology, University of Cambridge, Cambridge, UK., Michelotti GA; Metabolon, Morrisville, NC, USA., Arlt W; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK., Lotta LA; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Denaxas S; Institute of Health Informatics, University College London, London, UK.; Health Data Research UK, London, UK.; British Heart Foundation Data Science Centre, London, UK., Hemingway H; Institute of Health Informatics, University College London, London, UK.; Health Data Research UK, London, UK., Gamazon ER; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.; Clare Hall & MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Howson JMM; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK., Wood AM; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Hinxton, UK.; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.; MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK.; The Alan Turing Institute, London, UK., Danesh J; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Hinxton, UK.; Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK., Wareham NJ; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Hinxton, UK.; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Kastenmüller G; Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany., Fauman EB; Internal Medicine Research Unit, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA., Suhre K; Department of Biophysics and Physiology, Weill Cornell Medicine-Qatar, Doha, Qatar., Butterworth AS; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. asb38@medschl.cam.ac.uk.; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. asb38@medschl.cam.ac.uk.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Hinxton, UK. asb38@medschl.cam.ac.uk.; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK. asb38@medschl.cam.ac.uk., Langenberg C; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. Claudia.Langenberg@mrc-epid.cam.ac.uk.; Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany. Claudia.Langenberg@mrc-epid.cam.ac.uk.; Precision Healthcare University Research Institute, Queen Mary University of London, London, UK. Claudia.Langenberg@mrc-epid.cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2022 Nov; Vol. 28 (11), pp. 2321-2332. Date of Electronic Publication: 2022 Nov 10.
DOI: 10.1038/s41591-022-02046-0
Abstrakt: Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10 -11 ) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
(© 2022. The Author(s).)
Databáze: MEDLINE
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