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

Andrew A. Brown, 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, Petra J. M. Elders, 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, Miranda Mourby, 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, Søren Brunak, 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 () and Ana Viñuela ()
Additional contact information
Andrew A. Brown: University of Dundee
Juan J. Fernandez-Tajes: University of Oxford
Mun-gwan Hong: KTH - Royal Institute of Technology
Caroline A. Brorsson: Technical University of Denmark
Robert W. Koivula: University of Oxford
David Davtian: University of Dundee
Théo Dupuis: University of Dundee
Ambra Sartori: University of Geneva Medical School
Theodora-Dafni Michalettou: University of Newcastle
Ian M. Forgie: University of Dundee
Jonathan Adam: German Center for Diabetes Research (DZD)
Kristine H. Allin: University of Copenhagen
Robert Caiazzo: University of Lille, Inserm, Lille Pasteur Institute
Henna Cederberg: University of Eastern Finland
Federico De Masi: Technical University of Denmark
Petra J. M. Elders: Amsterdam Public Health research institute
Giuseppe N. Giordano: Lund University Diabetes Centre
Mark Haid: German Research Center for Environmental Health, Helmholtz Zentrum München
Torben Hansen: University of Copenhagen
Tue H. Hansen: University of Copenhagen
Andrew T. Hattersley: University of Exeter College of Medicine & Health
Alison J. Heggie: Newcastle University
Cédric Howald: University of Geneva Medical School
Angus G. Jones: University of Exeter College of Medicine & Health
Tarja Kokkola: University of Eastern Finland
Markku Laakso: University of Eastern Finland
Anubha Mahajan: University of Oxford
Andrea Mari: National Research Council
Timothy J. McDonald: Royal Devon and Exeter NHS Foundation Trust
Donna McEvoy: Royal Victoria Infirmary
Miranda Mourby: University of Oxford
Petra B. Musholt: Hoechst Industrial Park
Birgitte Nilsson: Technical University of Denmark
Francois Pattou: University of Lille, Inserm, Lille Pasteur Institute
Deborah Penet: University of Geneva Medical School
Violeta Raverdy: University of Lille, Inserm, Lille Pasteur Institute
Martin Ridderstråle: Lund University
Luciana Romano: University of Geneva Medical School
Femke Rutters: Epidemiology and Data Science, VUMC
Sapna Sharma: German Research Center for Environmental Health, Helmholtz Zentrum München
Harriet Teare: University of Oxford
Leen ‘t Hart: Epidemiology and Data Science, VUMC
Konstantinos D. Tsirigos: Technical University of Denmark
Jagadish Vangipurapu: University of Eastern Finland
Henrik Vestergaard: University of Copenhagen
Søren Brunak: Technical University of Denmark
Paul W. Franks: Lund University Diabetes Centre
Gary Frost: Imperial College London
Harald Grallert: German Center for Diabetes Research (DZD)
Bernd Jablonka: Sanofi Partnering, Sanofi-Aventis Deutschland GmbH
Mark I. McCarthy: University of Oxford
Imre Pavo: Eli Lilly Regional Operations Ges.m.b.H
Oluf Pedersen: Herlev and Gentofte University Hospital
Hartmut Ruetten: Sanofi Partnering, Sanofi-Aventis Deutschland GmbH
Mark Walker: University of Newcastle
Jerzy Adamski: National University of Singapore
Jochen M. Schwenk: KTH - Royal Institute of Technology
Ewan R. Pearson: University of Dundee
Emmanouil T. Dermitzakis: University of Geneva Medical School
Ana Viñuela: University of Newcastle

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40569-3

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