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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\n                    <jats:italic>trans<\/jats:italic>\n                    - and 19\n                    <jats:italic>cis<\/jats:italic>\n                    -acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of the\n                    <jats:italic>Atypical Chemokine Receptor 1 (ACKR1)<\/jats:italic>\n                    acting as scavenger for multiple chemokines and the role of\n                    <jats:italic>tumor necrosis factor receptor-associated factor 1 (TRAFD1)<\/jats:italic>\n                    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\n                    <jats:italic>cis<\/jats:italic>\n                    -MR using 2 independent proteomics datasets paired with colocalization revealed G-CSF\/CSF-3 and CXCL9\/MIG as potential causal mediators of asthma and Crohn\u2019s 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.\n                  <\/jats:p>","DOI":"10.1038\/s42003-025-07453-w","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T04:08:11Z","timestamp":1736482091000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3592-7191","authenticated-orcid":false,"given":"Marek J.","family":"Konieczny","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6126-8631","authenticated-orcid":false,"given":"Murad","family":"Omarov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Malik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7918-2040","authenticated-orcid":false,"given":"Tom G.","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian-Edgar","family":"Baumeister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2996-2652","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Bernhagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0654-387X","authenticated-orcid":false,"given":"Martin","family":"Dichgans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3507-3659","authenticated-orcid":false,"given":"Marios K.","family":"Georgakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,10]]},"reference":[{"key":"7453_CR1","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/s41571-021-00588-9","volume":"19","author":"DJ Propper","year":"2022","unstructured":"Propper, D. 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