Mapping pQTLs of circulating inflammatory proteins identifies drivers of immune-related disease risk and novel therapeutic targets
Author:
, Zhao Jing Hua, Stacey David, Eriksson Niclas, Macdonald-Dunlop Erin, Hedman Åsa K, Kalnapenkis Anette, Enroth StefanORCID, Cozzetto Domenico, Digby-Bell Jonathan, Marten Jonathan, Folkersen LasseORCID, Herder Christian, Jonsson Lina, Bergen Sarah E, Geiger Christian, Needham Elise J, Surendran Praveen, Paul Dirk SORCID, Polasek Ozren, Thorand Barbara, Grallert Harald, Roden Michael, Võsa Urmo, Esko Tonu, Hayward Caroline, Johansson ÅsaORCID, Gyllensten Ulf, Powell Nicholas, Hansson Oskar, Mattsson-Carlgren Niklas, Joshi Peter KORCID, Danesh John, Padyukov LeonidORCID, Klareskog Lars, Landén Mikael, Wilson James F, Siegbahn Agneta, Wallentin Lars, Mälarstig Anders, Butterworth Adam SORCID, Peters James EORCID,
Abstract
ABSTRACTCirculating proteins play key roles in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 15,150 participants. We identified 180 pQTLs, of which 50 were novel. Integration of pQTL data with eQTL and disease GWAS provided insights into pathogenesis, implicating lymphotoxin-alpha (LTA) in multiple sclerosis. Using Mendelian randomisation (MR), we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant causal roles for CD40 in rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Our results highlight novel potential therapeutic avenues, including CXCL5 in ulcerative colitis (UC), a finding supported by elevated gutCXCL5expression in UC patients. Our data provide a powerful resource to facilitate future drug target prioritization.
Publisher
Cold Spring Harbor Laboratory
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