Mapping pQTLs of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and novel therapeutic targets

Jing Hua Zhao; David Stacey; Niclas Eriksson; Erin Macdonald-Dunlop; Åsa K. Hedman; Anette Kalnapenkis; Stefan Enroth; Domenico Cozzetto; Jonathan L. Digby-Bell; Jonathan Marten; Lasse Folkersen; Christian Herder; Lina Jönsson; Sarah E. Bergen; Christian Gieger; Elise J. Needham; Praveen Surendran; Andres Metspalu; Lili A. Milani; Reedik Mägi; Mari Nelis; Georgi Hudjashov; Dirk S. Paul; Ozren Polašek; Barbara Thorand; Harald Grallert; Michael Roden; Urmo Võsa; Tõnu Esko; Caroline Hayward

doi:10.1038/s41590-023-01588-w

Genetic & Genomic MedicineNature ImmunologyAug 10, 2023

Peer-reviewed journal article

Mapping pQTLs of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and novel therapeutic targets

Jing Hua Zhao iD, David Stacey iD, Niclas Eriksson iD, Erin Macdonald-Dunlop iD, Åsa K. Hedman iD, Anette Kalnapenkis iD, Stefan Enroth iD, Domenico Cozzetto iD, Jonathan L. Digby-Bell iD, Jonathan Marten iD, Lasse Folkersen iD, Christian Herder iD, Lina Jönsson iD, Sarah E. Bergen iD, Christian Gieger iD, Elise J. Needham iD, Praveen Surendran iD, Andres Metspalu iD, Lili A. Milani iD, Reedik Mägi iD, Mari Nelis iD, Georgi Hudjashov iD, Dirk S. Paul iD, Ozren Polašek iD, Barbara Thorand iD, , James E. Peters iD

Abstract

Circulating 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 gut CXCL5 expression in UC patients. Our data provide a powerful resource to facilitate future drug target prioritization.

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