Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits
Year: 2023
Type: article
Study design: Observational Study
Abstract: Genetic variants identified by genome-wide association studies can contribute to disease risk by altering the production and abundance of mRNA, proteins and other molecules. However, the interplay between molecular intermediaries that define the pathway from genetic variation to disease is not well understood. Here, we evaluated the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3,029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant was associated with multiple molecular phenotypes over multiple genomic regions. We find varying proportions of shared genetic regulation across phenotypes, highest between expression and proteins (66.6%). We were able to recapitulate a substantial proportion of gene expression genetic regulation in a diverse set of 44 tissues, with a median of 88% shared associations for blood expression and 22.3% for plasma proteins. Finally, the genetic and molecular associations were represented in networks including 2,828 known GWAS variants. One sub-network shows the trans relationship between rs149007767 and RTEN , and identifies GRB10 and IKZF1 as candidates mediating genes. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants across different molecular phenotypes.
Source: Nature Communications
Authors: 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, 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
Institutions: University of Dundee, Ninewells Hospital, Centre for Human Genetics, University of Oxford, Science for Life Laboratory, KTH Royal Institute of Technology, University of Copenhagen, Novo Nordisk Foundation, Technical University of Denmark, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Geneva, SIB Swiss Institute of Bioinformatics, Institute of Genetics and Genomics in Geneva, Newcastle University, Helmholtz Munich, German Center for Diabetes Research, Inserm, Université de Lille, Institut Pasteur de Lille, University of Eastern Finland, Amsterdam Public Health, Amsterdam UMC Location Vrije Universiteit Amsterdam, Lund University, University of Exeter, National Research Council, Royal Devon & Exeter NHS Foundation Trust, Royal Victoria Infirmary, Sanofi (Germany), Technical University of Munich, Leiden University Medical Center, Steno Diabetes Center Copenhagen, Imperial College London, Genentech, Gentofte Hospital, Novo Nordisk Foundation Center for Basic Metabolic Research, Eli Lilly (United States), Servier (France), Institut de Recherches Internationales Servier (France), Boehringer Ingelheim (Germany), University of Westminster, Saarland University, University of Bath, Centre for Genomic Regulation, University of Tübingen, NIHR Exeter Clinical Research Facility, Universität Ulm, Eli Lilly (Germany), University of Ljubljana, National University of Singapore
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
OpenAlex ID: W4386027529