Cytokines are essential regulatory components of the immune system, and
their aberrant levels have been linked to many disease states. Despite
increasing evidence that cytokines operate in concert, many of the
physiological interactions between cytokines, and the shared genetic
architecture that underlies them, remain unknown. Here, we aimed to
identify and characterize genetic variants with pleiotropic effects on
cytokines. Using three population-based cohorts (n = 9,263), we
performed multivariate genome-wide association studies (GWAS) for a
correlation network of 11 circulating cytokines, then combined our
results in meta-analysis. We identified a total of eight loci
significantly associated with the cytokine network, of which two (PDGFRB
and ABO) had not been detected previously. In addition, conditional
analyses revealed a further four secondary signals at three known
cytokine loci. Integration, through the use of Bayesian colocalization
analysis, of publicly available GWAS summary statistics with the
cytokine network associations revealed shared causal variants between
the eight cytokine loci and other traits; in particular, cytokine
network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic
effects on the production of immune-related proteins, on metabolic
traits such as lipoprotein and lipid levels, on blood-cell-related
traits such as platelet count, and on disease traits such as coronary
artery disease and type 2 diabetes.