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

2023; Nature Portfolio; Volume: 14; Issue: 1 Linguagem: Inglês

10.1038/s41467-023-40569-3

2041-1723

Andrew Brown, Juan Fernández‐Tajes, Mun‐Gwan Hong, Caroline Brorsson, Robert W. Koivula, David Davtian, Théo Dupuis, Ambra Sartori, Theodora-Dafni Michalettou, Ian Forgie, Jonathan Adam, Kristine H. Allin, Robert Caïazzo, Henna Cederberg, Federico De Masi, Petra J. M. Elders, Giuseppe N. Giordano, Mark Haid, Torben Hansen, Tue H. Hansen, Andrew T. Hattersley, Alison 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, François Pattou, Deborah Penet, Violeta Raverdy, Martin Ridderstråle, Luciana Romano, Femke Rutters, Sapna Sharma, Harriet Teare, Leen M. ‘t Hart, Konstantinos D. Tsirigos, Jagadish Vangipurapu, Henrik Vestergaard, Søren Brunak, Paul W. Franks, Gary Frost, Harald Grallert, Bernd Jablonka, Mark I. McCarthy, Imre Pávó, Oluf Pedersen, Hartmut Ruetten, Mark Walker, Kofi P. Adragni, Rosa Lundbye Allesøe, Anna A. Artati, Manimozhiyan Arumugam, Naeimeh Atabaki‐Pasdar, Tania Baltauss, Karina Banasik, Anna Barnett, Patrick Baum, Jimmy D. Bell, Joline W. J. Beulens, Susanna Bianzano, Roberto Bizzotto, Amélie Bonnefond, Louise Cabrelli, Matilda Dale, Adem Y. Dawed, Nathalie de Préville, Koen F. Dekkers, Harshal Deshmukh, Christiane Dings, Louise A. Donnelly, Avirup Dutta, Beate Ehrhardt, Line Engelbrechtsen, Rebeca Eriksen, Yong Fan, Jorge Ferrer, Hugo Fitipaldi, Annemette Forman, Andreas Fritsche, Philippe Froguel, Johann Gassenhuber, Stephen Gough, Ulrike Graefe‐Mody, Rolf Grempler, Lenka Groeneveld, Leif Groop, Valborg Guðmundsdóttir, Ramneek Gupta, Anita M. Hennige, Anita Hill, Reinhard W. Holl, Michelle Hudson, Ulrik Plesner Jacobsen, Christopher Jennison, Joachim Johansen, Anna Jonsson, Tugce Karaderi, Jane Kaye, Gwen Kennedy, Maria Klintenberg, Teemu Kuulasmaa, Thorsten Lehr, Heather Loftus, Agnete Troen Lundgaard, Gianluca Mazzoni, Nicky McRobert, Ian McVittie, Rachel Nice, Claudia Nicolay, Giel Nijpels, Nicholette D. Palmer, Helle K. Pedersen, Mandy H. Perry, Hugo Pomares‐Millan, Cornelia Prehn, Anna Ramisch, Simon Rasmussen, Neil Robertson, Marianne Rodriquez, Peter Sáckett, Nina Scherer, Nisha Shah, Iryna Sihinevich, Roderick C. Slieker, Nadja B. Søndertoft, Birgit Steckel-Hamann, Melissa K. Thomas, Cecilia Engel Thomas, E. Louise Thomas, Barbara Thorand, Claire E. Thorne, J. Tillner, Andrea Tura, Mathias Uhlén, Nienke van Leeuwen, Sabine van Oort, Hélène Verkindt, Josef Korbinian Vogt, Peter Wad Sackett, Agata Wesolowska‐Andersen, Brandon Whitcher, Margaret W. White, Jerzy Adamski, Jochen M. Schwenk, Ewan R. Pearson, Emmanouil T. Dermitzakis, Ana Viñuela,

Bioinformatics and Genomic Networks

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.