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

Søren Brunak, Petra B Musholt, Birgitte Nilsson, Francois Pattou, Deborah Penet, Violeta Raverdy, Martin Ridderstråle, Luciana Romano, Femke Rutters, Sapna Sharma, Harriet Teare, Leen 't Hart, Konstantinos D Tsirigos, Jagadish Vangipurapu, Henrik Vestergaard, Miranda Mourby, Paul W Franks, Gary Frost, Harald Grallert, Bernd Jablonka, Mark I McCarthy, Imre Pavo, Oluf Pedersen, Hartmut Ruetten, Mark Walker, Jerzy Adamski, Jochen M Schwenk, Ewan R Pearson, Emmanouil T Dermitzakis, Ana Viñuela, Petra J M Elders, Juan J Fernandez-Tajes, Mun-Gwan Hong, Caroline A Brorsson, Robert W Koivula, David Davtian, Théo Dupuis, Ambra Sartori, Theodora-Dafni Michalettou, Ian M Forgie, Jonathan Adam, Kristine H Allin, Robert Caiazzo, Henna Cederberg, Federico De Masi, Andrew A Brown, Giuseppe N Giordano, Mark Haid, Torben Hansen, Tue H Hansen, Andrew T Hattersley, Alison J Heggie, Cédric Howald, Angus G Jones, Tarja Kokkola, Markku Laakso, Anubha Mahajan, Andrea Mari, Timothy J McDonald, Donna McEvoy

Journal: Nature communications 2023;14(1):5062

PMID: 37604891

Abstract

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.

Address: Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom.; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom.; Science for Life Laboratory, School of Biotechnology, KTH - Royal Institute of Technology, Solna, SE-171 21, Sweden.; 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.; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, OX3 7LJ, United Kingdom.; 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.; Biosciences Institute, Faculty of Medical Sciences, University of Newcastle, Newcastle upon Tyne, NE1 4EP, United Kingdom.; 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.; The Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, DK-2100, Denmark.; University of Lille, Inserm, Lille Pasteur Institute, Lille, France.; Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.; Department of General Practice, Amsterdam UMC- location Vumc, Amsterdam Public Health research institute, Amsterdam, The Netherlands.; Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Malmö, Sweden.; Metabolomics and Proteomics Core, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, 85764, Germany.; Department of Clinical and Biomedical Sciences, University of Exeter College of Medicine & Health, Exeter, EX25DW, United Kingdom.; Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.; Institute of Neuroscience, National Research Council, Padova, 35127, Italy.; Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, EX2 5DW, United Kingdom.; Diabetes Research Network, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom.; Nuffield Department of Population Health, Centre for Health, Law and Emerging Technologies (HeLEX), University of Oxford, Oxford, OX2 7DD, United Kingdom.; Global Development, Sanofi-Aventis Deutschland GmbH, Hoechst Industrial Park, Frankfurt am Main, 65926, Germany.; Department of Clinical Science, Lund University, Malmö, Sweden.; Epidemiology and Data Science, VUMC, Amsterdam, The Netherlands.; Food Chemistry and Molecular and Sensory Science, Technical University of Munich, München, Germany.; Centre for Health Law and Emerging Technologies, Department of Population Health, University of Oxford, Old Road Campus, Oxford, OX3 7DQ, United Kingdom.; 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.; Steno Diabetes Center Copenhagen, Copenhagen, Denmark.; Nutrition and Dietetics Research Group, Imperial College London, London, SW7 2AZ, United Kingdom.; Sanofi Partnering, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, 65926, Germany.; GENENTECH, 1 DNA Way, San Francisco, CA, 94080, USA.; Eli Lilly Regional Operations Ges.m.b.H, Vienna, 1030, Austria.; 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.; Translational and Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle, Newcastle upon Tyne, United Kingdom.; 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.; Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, 1211, Switzerland. [email protected].; Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, 1211, Switzerland. [email protected].; Swiss Institute of Bioinformatics, Geneva, 1211, Switzerland. [email protected].; Biosciences Institute, Faculty of Medical Sciences, University of Newcastle, Newcastle upon Tyne, NE1 4EP, United Kingdom. [email protected].
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