Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Jing Hua Zhao(University of Cambridge), David Stacey(University of South Australia), Niclas Eriksson(Uppsala University), Erin Macdonald-Dunlop(University of Edinburgh), Åsa K. Hedman(Karolinska Institutet), Anette Kalnapenkis(University of Cambridge), Stefan Enroth(Uppsala University), Domenico Cozzetto(Imperial College London), Jonathan Digby‐Bell(King's College London), Jonathan Marten(University of Cambridge), Lasse Folkersen, Christian Herder(Düsseldorf University Hospital), Lina Jönsson(University of Gothenburg), Sarah E. Bergen(Karolinska Institutet), Christian Gieger(Helmholtz Zentrum München), Elise J. Needham(University of Cambridge), Praveen Surendran(University of Cambridge), Andres Metspalu(University of Tartu), Lili Milani(University of Tartu), Reedik Mägi(University of Tartu), Mari Nelis(University of Tartu), Georgi Hudjašov(University of Tartu), Dirk S. Paul(AstraZeneca (United Kingdom)), Ozren Polašek(University of Split), Barbara Thorand(Helmholtz Zentrum München), Harald Grallert(Helmholtz Zentrum München), Michael Roden(Düsseldorf University Hospital), Urmo Võsa(University of Tartu), Tõnu Esko(University of Tartu), Caroline Hayward(Western General Hospital), Åsa Johansson(Uppsala University), Ulf Gyllensten(Uppsala University), Nick Powell(Imperial College London), Oskar Hansson(Lund University), Niklas Mattsson(Lund University), Peter K. Joshi(University of Edinburgh), John Danesh(NHS Blood and Transplant), Leonid Padyukov(Karolinska University Hospital), Lars Klareskog(Karolinska University Hospital), Mikael Landén(Karolinska Institutet), James F. Wilson(Western General Hospital), Agneta Siegbahn(Uppsala University), Lars Wallentin(Uppsala University), Anders Mälarstig(Karolinska Institutet), Adam S. Butterworth(NHS Blood and Transplant), James E. Peters(British Heart Foundation)
Nature Immunology
August 10, 2023
10.1038/s41590-023-01588-w
Cited by 719Open Access
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Abstract

Circulating proteins have important functions 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 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.

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