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. HansenAndrew 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, Kofi Adragni, Rosa Lundbye L. Allesøe, Anna A. Artati, Manimozhiyan Arumugam, Naeimeh Atabaki-Pasdar, Tania Baltauss, Karina Banasik, Anna L. Barnett, Patrick Baum, Jimmy D. Bell, Joline W. Beulens, Susanna B. Bianzano, Roberto Bizzotto, Amelie Bonnefond, Louise Cabrelli, Matilda Dale, Adem Y. Dawed, Nathalie de Preville, Koen F. Dekkers, Harshal A. Deshmukh, Christiane Dings, Louise 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 Gudmundsdóttir, Ramneek Gupta, Anita M.H. Hennige, Anita V. 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 T. Lundgaard, Gianluca Mazzoni, Nicky McRobert, Ian McVittie, Rachel Nice, Claudia Nicolay, Giel Nijpels, Colin N. Palmer, Helle K. Pedersen, Mandy H. Perry, Hugo Pomares-Millan, Cornelia P. Prehn, Anna Ramisch, Simon Rasmussen, Neil Robertson, Marianne Rodriquez, Peter Sackett, Nina Scherer, Nisha Shah, Iryna Sihinevich, Roderick C. Slieker, Nadja B. Sondertoft, Birgit Steckel-Hamann, Melissa K. Thomas, Cecilia Engel E. Thomas, Elizabeth Louise L. Thomas, Barbara Thorand, Claire E. Thorne, Joachim Tillner, Andrea Tura, Mathias Uhlen, Nienke van Leeuwen, Sabine van Oort, Helene Verkindt, Josef Vogt, Peter W. Wad Sackett, Agata Wesolowska-Andersen, Brandon Whitcher, Margaret W. White, Jerzy Adamski, Jochen M. Schwenk, Ewan R. Pearson, Emmanouil T. Dermitzakis, Ana Viñuela

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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.

Original languageEnglish
Article number5062
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

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