Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.

Autor: Brown AA; Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom., Fernandez-Tajes JJ; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom., Hong MG; Science for Life Laboratory, School of Biotechnology, KTH - Royal Institute of Technology, Solna, SE-171 21, Sweden., Brorsson CA; Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2100, Denmark., Koivula RW; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, OX3 7LJ, United Kingdom., Davtian D; Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom., Dupuis T; Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom., Sartori A; Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, 1211, Switzerland.; Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, 1211, Switzerland.; Swiss Institute of Bioinformatics, Geneva, 1211, Switzerland., Michalettou TD; Biosciences Institute, Faculty of Medical Sciences, University of Newcastle, Newcastle upon Tyne, NE1 4EP, United Kingdom., Forgie IM; Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom., Adam J; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany.; Research Unit of Molecular Epidemiology, Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, 85764, Germany., Allin KH; The Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, DK-2100, Denmark., Caiazzo R; University of Lille, Inserm, Lille Pasteur Institute, Lille, France., Cederberg H; Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland., De Masi F; Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark., Elders PJM; Department of General Practice, Amsterdam UMC- location Vumc, Amsterdam Public Health research institute, Amsterdam, The Netherlands., Giordano GN; Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Malmö, Sweden., Haid M; Metabolomics and Proteomics Core, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, 85764, Germany., Hansen T; The Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, DK-2100, Denmark., Hansen TH; The Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, DK-2100, Denmark., Hattersley AT; Department of Clinical and Biomedical Sciences, University of Exeter College of Medicine & Health, Exeter, EX25DW, United Kingdom., Heggie AJ; Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom., Howald C; Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, 1211, Switzerland.; Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, 1211, Switzerland.; Swiss Institute of Bioinformatics, Geneva, 1211, Switzerland., Jones AG; Department of Clinical and Biomedical Sciences, University of Exeter College of Medicine & Health, Exeter, EX25DW, United Kingdom., Kokkola T; Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland., Laakso M; Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland., Mahajan A; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom., Mari A; Institute of Neuroscience, National Research Council, Padova, 35127, Italy., McDonald TJ; Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, EX2 5DW, United Kingdom., McEvoy D; Diabetes Research Network, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom., Mourby M; Nuffield Department of Population Health, Centre for Health, Law and Emerging Technologies (HeLEX), University of Oxford, Oxford, OX2 7DD, United Kingdom., Musholt PB; Global Development, Sanofi-Aventis Deutschland GmbH, Hoechst Industrial Park, Frankfurt am Main, 65926, Germany., Nilsson B; Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark., Pattou F; University of Lille, Inserm, Lille Pasteur Institute, Lille, France., Penet D; Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, 1211, Switzerland.; Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, 1211, Switzerland.; Swiss Institute of Bioinformatics, Geneva, 1211, Switzerland., Raverdy V; University of Lille, Inserm, Lille Pasteur Institute, Lille, France., Ridderstråle M; Department of Clinical Science, Lund University, Malmö, Sweden., Romano L; Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, 1211, Switzerland.; Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, 1211, Switzerland.; Swiss Institute of Bioinformatics, Geneva, 1211, Switzerland., Rutters F; Epidemiology and Data Science, VUMC, Amsterdam, The Netherlands., Sharma S; Research Unit of Molecular Epidemiology, Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, 85764, Germany.; Food Chemistry and Molecular and Sensory Science, Technical University of Munich, München, Germany., Teare H; Centre for Health Law and Emerging Technologies, Department of Population Health, University of Oxford, Old Road Campus, Oxford, OX3 7DQ, United Kingdom., 't Hart L; Epidemiology and Data Science, VUMC, Amsterdam, The Netherlands.; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.; Department of Biomedical Data Sciences, Molecular Epidemiology section, Leiden University Medical Center, Leiden, The Netherlands., Tsirigos KD; Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark., Vangipurapu J; Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland., Vestergaard H; The Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, DK-2100, Denmark.; Steno Diabetes Center Copenhagen, Copenhagen, Denmark., Brunak S; Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2100, Denmark., Franks PW; Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Malmö, Sweden., Frost G; Nutrition and Dietetics Research Group, Imperial College London, London, SW7 2AZ, United Kingdom., Grallert H; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany.; Research Unit of Molecular Epidemiology, Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, 85764, Germany., Jablonka B; Sanofi Partnering, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, 65926, Germany., McCarthy MI; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom.; GENENTECH, 1 DNA Way, San Francisco, CA, 94080, USA., Pavo I; Eli Lilly Regional Operations Ges.m.b.H, Vienna, 1030, Austria., Pedersen O; Center for Clinical Metabolic Research, Herlev and Gentofte University Hospital, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2100, Denmark., Ruetten H; Sanofi Partnering, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, 65926, Germany., Walker M; Translational and Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle, Newcastle upon Tyne, United Kingdom., Adamski J; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.; Institute of Experimental Genetics, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, 85764, Germany.; Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia., Schwenk JM; Science for Life Laboratory, School of Biotechnology, KTH - Royal Institute of Technology, Solna, SE-171 21, Sweden., Pearson ER; Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom., Dermitzakis ET; Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, 1211, Switzerland. emmanouil.dermitzakis@unige.ch.; Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, 1211, Switzerland. emmanouil.dermitzakis@unige.ch.; Swiss Institute of Bioinformatics, Geneva, 1211, Switzerland. emmanouil.dermitzakis@unige.ch., Viñuela A; Biosciences Institute, Faculty of Medical Sciences, University of Newcastle, Newcastle upon Tyne, NE1 4EP, United Kingdom. ana.vinuela@newcastle.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Aug 21; Vol. 14 (1), pp. 5062. Date of Electronic Publication: 2023 Aug 21.
DOI: 10.1038/s41467-023-40569-3
Abstrakt: We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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