Multi-cohort proteogenomic analyses reveal genetic effects across the proteome and diseasome

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.

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Journal
Cell
Published
2026-05-01
DOI
https://doi.org/10.1016/j.cell.2026.03.049
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
0.00

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article

Multi-cohort proteogenomic analyses reveal genetic effects across the proteome and diseasome

Anette Kalnapenkis, Jingyuan Fu, Themistocles L. Assimes, Lucija Klarić et al.
Cell
Genetic Associations and Epidemiology
article

Multi-cohort proteogenomic analyses reveal genetic effects across the proteome and diseasome

Anette Kalnapenkis, Jingyuan Fu, Themistocles L. Assimes, Lucija Klarić, Bram Peter Prins, Grace Png, Morten Bøttcher, Sophia Björkander, Sarah E. Harris, Federico Murgia, Jurgis Kuliesius, A Siegbahn, Shixian Hu, Peter Möller, Per Eriksson, Pik Fang Kho, Julia Kraft, Anna Ramisch, Mine Koprulu, Elsa Valdés‐Márquez, Niklas Mattsson, Mette Nyegaard, Erik Melén, K Czene, Christina Jern, Simon Kebede Merid, Saredo Said, Aida Ferreiro-Iglesias, Erin Macdonald-Dunlop, Ziad Hijazi, L. Repetto, Chibuzor Franklin Ogamba, P.F. Hall, Ozren Polašek, Simon Riddington Cox, Lars Wallentin, John Danesh, Adam Stuart Butterworth, Åsa K. Hedman, Leonhard Kohleick, E R Pearson, L Lind, J Petrie, J C Hopewell, Robert F. Hillary, J B J van Meurs, Z M Chen, M Roden, C Herder, Sölve Elmståhl, Karl Smith-Byrne, Philipp Mertins, Young-Chan Park, Lina Jonsson, Nicholas John Wareham, Ana Viñuela, Christian Gieger, Jochen M. Schwenk, Johan Sundström, Kelly Cho, Robert Joseph Clarke, Mikael Landén, Barbara Thorand, James Peters, Xia Shen, J. Michael Gaziano, Andreas Göteson, Tõnu Esko, Costanza L. Vallerga, Robin G. Walters, Karl Michaëlsson, Åsa Johansson, Karsten Suhre, Mohsen Ghanbari, Stefan Gustafsson, Liming Li, Harald Grallert, Jirong Long, Caroline Hayward, Paul William Franks, J. Gustav Smith, Niclas Eriksson, George Dedoussis, Jian’an Luan, Johan Ärnlöv, Natalia Hernandez-Pacheco, Nicola Dorothy Kerrison, Marc James Gunter, Hanna M. Björck, Tara M. Stanne, Joachim Eduard Weber, Fahim Abbasi, Brian Richard Ferolito, Shih-Jen Hwang, Oskar Hansson, Urmo Võsa, Palle Duun Rohde, Daniel Levy, Arthur Gilly, Stephan Ripke
article en

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.

Cell
Statens Serum Institut (DK), University of Geneva (CH), Dalarna University (SE), Uppsala University (SE), NHS Lothian (GB), University Medical Center Groningen (NL), Karolinska University Hospital (SE), Uppsala University Hospital (SE), Alnylam Pharmaceuticals (United States) (US), Sun Yat-sen University (CN), Queen Mary University of London (GB), University of Dundee (GB), Malmö University (SE), Lund University (SE), Peking University (CN), Max Delbrück Center (DE), Cornell University (US), University of Cambridge (GB), Science for Life Laboratory (SE), Sahlgrenska University Hospital (SE), VA Boston Healthcare System (US), Erasmus MC (NL), Aarhus University Hospital (DK), Edinburgh Cancer Research (GB), Karolinska Institutet (SE), Helmholtz Zentrum München (DE), Lander Institute (IL), British Heart Foundation (GB), Harokopio University of Athens (GR), Humboldt-Universität zu Berlin (DE), University of Oxford (GB), Düsseldorf University Hospital (DE), Pfizer (Sweden) (SE), Stockholm South General Hospital (SE), Novo Nordisk (Finland) (FI), The George Institute for Global Health (AU), Framingham Heart Study (US), The First Affiliated Hospital, Sun Yat-sen University (CN), Stanford Medicine (US), Centre for Global Health Research (CA), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Deutsches Diabetes-Zentrum e.V. (DE), Weill Cornell Medical College in Qatar (QA), MRC Epidemiology Unit (GB), Institute of Genetics and Cancer (GB), German Center for Diabetes Research (DE), Centre international de recherche sur le cancer (FR), Heinrich Heine University Düsseldorf (DE), Imperial College London (GB), University of Tartu (EE), University of Glasgow (GB), Ludwig-Maximilians-Universität München (DE), KTH Royal Institute of Technology (SE), University of Gothenburg (SE), Aalborg University (DK), Vanderbilt University Medical Center (US), Erasmus University Rotterdam (NL), University of Split (HR), Stanford University (US), University of Edinburgh (GB)
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, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Hjärnfonden, Hjärt-Lungfonden, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Hrvatska Zaklada za Znanost, 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, 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
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Genetic Associations and Epidemiology
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