Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals. We detected 359 significant associations between cytokine levels and variants in 169 independent loci, including 150 trans- and 19 cis-acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of ACKR1 acting as scavenger for multiple chemokines and the role of TRAFD1 in modulating the cytokine storm triggered by TNF signaling. Applying Mendelian randomization (MR), we detected a network of complex cytokine interconnections with TNF-b, VEGF, and IL-1ra exhibiting pleiotropic downstream effects on multiple cytokines. Drug target cis-MR paired with colocalization revealed G-CSF/CSF-3 and CXCL9/MIG as potential causal mediators of asthma and Crohns disease, respectively, but also a potentially protective role of TNF-b in multiple sclerosis. Our results provide an overview of the genetic architecture of circulating cytokines and could guide the development of targeted immunotherapies.

The authors declare the following competing interests: MJK is an employee of Alexion Pharmaceuticals, AstraZeneca Rare Disease unrelated to this work. TGR is an employee of GlaxoSmithKline unrelated to this work.

This work is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) by an Emmy Noether grant (GZ: GE 3461/2-1, ID 512461526 to MG), by a clinician-scientist grant to MG and project grants to JB and MD from the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198), and by CRC1123 project A3 to JB. Additional support comes from a research grant from the Fritz-Thyssen Foundation (Ref. 10.22.2.024MN to MG) and a research fellowship by the Hertie Foundation (Hertie Network of Excellence in Clinical Neuroscience, ID P1230035 to MG).

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Source data was openly available before the initiation of the study. Data can be obtained from the following websites: https://data.bris.ac.uk/data/dataset/3g3i5smgghp0s2uvm1doflkx9x https://zenodo.org/record/2615265#.Y_osx62ZMuX https://download.decode.is/form/folder/proteomics www.cardiogramplusc4d.org http://www.megastroke.org/ http://www.diagram-consortium.org/downloads.html http://bcac.ccge.medschl.cam.ac.uk/bcacdata/ https://data.bris.ac.uk/data/dataset/aed0u12w0ede20olb0m77p4b9 https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000876.v1.p1 https://github.com/Wittelab/pancancer_pleiotropy http://results.globalbiobankmeta.org/ https://www.ibdgenetics.org/ https://www.ncbi.nlm.nih.gov/gap/advanced_search/?TERM=phs001306.v1.p1 https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000275.v1.p1 http://plaza.umin.ac.jp/~yokada/datasource/software.htm http://ukb-ppp.gwas.eu

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GWAS meta-analysis summary statistics will be available at GWAS catalog