Multi-cohort proteogenomic analyses reveal genetic effects across the proteome and diseasome
Year: 2026
Type: article
Study design: Observational Study
Abstract: Understanding the genetic regulation of circulating protein levels can provide new insights into disease mechanisms. Here, we present the largest proteogenomic study to date (n = 78,664 participants across 38 studies), identifying >24,000 protein quantitative trait loci (QTLs) associated with 1,116 proteins, acting near to (n = 5,040) or distant (n = 19,698) from the cognate gene. Using machine learning-guided effector gene assignment, we provide genetic evidence for pathways, cell types, and tissues that modulate circulating protein levels, highlighting N-linked glycosylation as an important regulatory pathway. We demonstrate that genetic instruments of protein production/function ("cis") versus modulation ("trans") reveal distinct phenotypic insights. We identify proteins as candidates for drug targets and engagement (e.g., plasma furin and cardiovascular diseases) by comparing cis-based genetic evidence with protein-disease associations. Systematic triangulation of trans-protein QTLs (pQTLs) with genetic and protein associations across many diseases highlights potential drug repurposing opportunities, e.g., tyrosine kinase 2 (TYK2) inhibitors for rheumatoid arthritis. Our multi-cohort meta-analyses generate proteogenomic insights into disease mechanisms and new treatment opportunities.
Source: Cell
Authors: Mine Koprulu, Karl Smith-Byrne, Brian Richard Ferolito, Erin Macdonald-Dunlop, Jian’an Luan, Åsa K. Hedman, Chibuzor Franklin Ogamba, Jurgis Kuliesius, Linda Repetto, Anna Ramisch, Fahim Abbasi, Johan Ärnlöv, Themistocles L. Assimes, Hanna M. Björck, Sophia Björkander, Morten Böttcher, Adam Stuart Butterworth, Zhengming Chen, Kelly Cho, Robert Joseph Clarke, Simon Riddington Cox, Kamila Czene, John Danesh, George Dedoussis, Sölve Elmståhl, Niclas Eriksson, Per Eriksson, Tõnu Esko, Aida Ferreiro-Iglesias, Paul William Franks, Jingyuan Fu, J. Michael Gaziano, Mohsen Ghanbari, Christian Gieger, Arthur Gilly, Harald Grallert, Marc James Gunter, Stefan Gustafsson, Andreas Göteson, Per Frans Leonard Hall, Oskar Hansson, Sarah Elizabeth Harris, Caroline Hayward, Christian Herder, Natalia Hernandez-Pacheco, Ziad Hijazi, Robert F. Hillary, Jemma Caroline Hopewell, Shixian Hu, Shih-Jen Hwang, Christina Jern, Åsa Johansson, Lina Jonsson, Anette Kalnapenkis, Nicola Dorothy Kerrison, Pik Fang Kho, Lucija Klaric, Leonhard Kohleick, Julia Kraft, Mikael Landén, Daniel Levy, Liming Li, Lars Lind, Jirong Long, Niklas Mattsson-Carlgren, Erik Melén, Simon Kebede Merid, Philipp Mertins, Karl Michaëlsson, Peter Loof Møller, Federico Murgia, Mette Nyegaard, Young-Chan Park, Ewan Pearson, James Peters, John Ross Petrie, Grace Png, Ozren Polašek, Bram Peter Prins, Stephan Ripke, Michael Roden, Palle Duun Rohde, Saredo Said, Xia Shen, Jochen M. Schwenk, Agneta Siegbahn, J. Gustav Smith, Tara M. Stanne, Karsten Suhre, Johan Sundström, Barbara Thorand, Elsa Valdes-Marquez, Costanza L. Vallerga, Joyce B.J. van Meurs, Ana Viñuela, Urmo Võsa, Lars Wallentin, Robin G. Walters, Nicholas John Wareham, Joachim Eduard Weber, Rinse Karel Weersma, James F. Wilson, Simon Winther, Summaira Yasmeen, Daniela Zanetti, Eleftheria Zeggini, Jing Hua Zhao, Alexandra Zhernakova, Daria V. Zhernakova, Matthias Ziehm, Benedikt Mathias Kessler, Alexandre C. Pereira, Anders Mälarstig, Maik Pietzner, Claudia Langenberg
Institutions: Queen Mary University of London, University of Cambridge, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, MRC Epidemiology Unit, Charité - Universitätsmedizin Berlin, University of Oxford, VA Boston Healthcare System, Karolinska Institutet, Pfizer (Sweden), University of Edinburgh, University of Tartu, University of Geneva, Stanford Medicine, Stanford University, Dalarna University, Karolinska University Hospital, Aarhus University, British Heart Foundation, Health Data Research UK, Addenbrooke's Hospital, Harvard University, Mass General Brigham, Wellcome Sanger Institute, Harokopio University of Athens, Lund University, Uppsala University, Centre international de recherche sur le cancer, University Medical Center Groningen, Brigham and Women's Hospital, Erasmus MC, Helmholtz Munich, German Center for Diabetes Research, Imperial College London, University of Gothenburg, Stockholm South General Hospital, Institute of Genetics and Cancer, Düsseldorf University Hospital, Deutsches Diabetes-Zentrum e.V., Heinrich Heine University Düsseldorf, Sun Yat-sen University, The First Affiliated Hospital, Sun Yat-sen University, Boston University, National Heart, Lung, and Blood Institute, Sahlgrenska University Hospital, Alnylam Pharmaceuticals (United States), MRC Human Genetics Unit, Broad Institute, Stanley Center for Psychiatric Research, Deutsches Zentrum für Psychische Gesundheit, Massachusetts Institute of Technology, National Institutes of Health, Framingham Heart Study, Peking University, Vanderbilt University Medical Center, Max Delbrück Center, Aalborg University, Statens Serum Institut, University of Dundee, University of Glasgow, University of Split, Fudan University, State Key Laboratory of Genetic Engineering, Greater Bay Area Institute of Precision Medicine, Science for Life Laboratory, KTH Royal Institute of Technology, Skåne University Hospital, Weill Cornell Medicine, UNSW Sydney, The George Institute for Global Health, Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München, Humboldt-Universität zu Berlin, German Centre for Cardiovascular Research, Center for Stroke Research Berlin, Freie Universität Berlin, University of Groningen, Regionshospitalet Herning, National Research Council, TUM Klinikum, Technical University of Munich, Stiftung Charité, Max Planck Institute for Molecular Genetics
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,400
Funders: Stanley Medical Research Institute, Qatar Foundation, European Respiratory Society, Centre International de Recherche sur le Cancer, Wellcome Trust, Deutsches Zentrum für Herz-Kreislaufforschung, UK Research and Innovation, Cancer Research UK, British Heart Foundation, Royal Society, European Commission, Agence Nationale de la Recherche, Stiftelsen för Strategisk Forskning, National Natural Science Foundation of China, Eesti Teadusagentuur, Bundesministerium für Bildung und Forschung, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Hjärnfonden, Hjärt-Lungfonden, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Hrvatska Zaklada za Znanost, China Scholarship Council, Ministère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche, Gates Cambridge Trust, China Academy of Chinese Medical Sciences, ReumaNederland, Institut National Du Cancer, Ministarstvo Znanosti, Obrazovanja i Sporta, Novo Nordisk Fonden, Skånes universitetssjukhus, Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek, National Institutes of Health, Parkinsonfonden, Qatar National Research Fund, HORIZON EUROPE Framework Programme, Medical Research Council, European Research Council, Key Technologies Research and Development Program, National Key Research and Development Program of China Stem Cell and Translational Research, Helmholtz Zentrum München, NIHR Cambridge Biomedical Research Centre, National Heart, Lung, and Blood Institute, National Institute of Environmental Health Sciences, FP7 Coordination of Research Activities, Health Data Research UK
Award: G6763456886
OpenAlex ID: W7160378356