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 Crohn’s 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. ### Competing Interest Statement 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. ### Funding Statement 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). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Source data was openly available before the initiation of the study. Data can be obtained from the following websites: [www.cardiogramplusc4d.org][1] I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes GWAS meta-analysis summary statistics will be available at GWAS catalog [1]: http://www.cardiogramplusc4d.org