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