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.
Authors
Koprulu Koprulu, Smith-Byrne Smith-Byrne, Ferolito Ferolito, Macdonald-Dunlop Macdonald-Dunlop, Luan Luan, Hedman Hedman, Ogamba Ogamba, Kuliesius Kuliesius, Repetto Repetto, Ramisch Ramisch, Abbasi Abbasi, Ärnlöv Ärnlöv, Assimes Assimes, , Björck Björck, Björkander Björkander, Böttcher Böttcher, Butterworth Butterworth, Chen Chen, Cho Cho, Clarke Clarke, Cox Cox, Czene Czene, Danesh Danesh, Dedoussis Dedoussis, Elmståhl Elmståhl, Eriksson Eriksson, Eriksson Eriksson, Esko Esko, , Ferreiro-Iglesias Ferreiro-Iglesias, Franks Franks, Fu Fu, Gaziano Gaziano, Ghanbari Ghanbari, Gieger Gieger, Gilly Gilly, Grallert Grallert, Gunter Gunter, Gustafsson Gustafsson, Göteson Göteson, Hall Hall, Hansson Hansson, Harris Harris, Hayward Hayward, Herder Herder, Hernandez-Pacheco Hernandez-Pacheco, Hijazi Hijazi, Hillary Hillary, Hopewell Hopewell, Hu Hu, Hwang Hwang, Jern Jern, Johansson Johansson, Jonsson Jonsson, Kalnapenkis Kalnapenkis, Kerrison Kerrison, Kho Kho, Klaric Klaric, Kohleick Kohleick, Kraft Kraft, Landén Landén, Levy Levy, Li Li, Lind Lind, Long Long, Mattsson-Carlgren Mattsson-Carlgren, Melén Melén, Merid Merid, Mertins Mertins, Michaëlsson Michaëlsson, Møller Møller, Murgia Murgia, Nyegaard Nyegaard, Park Park, Pearson Pearson, Peters Peters, Petrie Petrie, Png Png, Polašek Polašek, Prins Prins, Ripke Ripke, Roden Roden, Rohde Rohde, Said Said, , Shen Shen, Schwenk Schwenk, Siegbahn Siegbahn, Smith Smith, Stanne Stanne, Suhre Suhre, Sundström Sundström, Thorand Thorand, Valdes-Marquez Valdes-Marquez, Vallerga Vallerga, van Meurs van Meurs, Viñuela Viñuela, Võsa Võsa, Wallentin Wallentin, Walters Walters, Wareham Wareham, Weber Weber, Weersma Weersma, Wilson Wilson, Winther Winther, Yasmeen Yasmeen, Zanetti Zanetti, Zeggini Zeggini, Zhao Zhao, Zhernakova Zhernakova, Zhernakova Zhernakova, Ziehm Ziehm, Kessler Kessler, Pereira Pereira, Mälarstig Mälarstig, Pietzner Pietzner, Langenberg Langenberg
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