Multivariate Genome-wide Association Analysis of a Cytokine Network Reveals Variants with Widespread Immune, Haematological, and Cardiometabolic Pleiotropy.
Nath, Artika P
Huang, Qin Qin
Teo, Shu Mei
Ahola-Olli, Ari V
Havulinna, Aki S
Viikari, Jorma S
Raitakari, Olli T
American journal of human genetics
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Nath, A. P., Ritchie, S., Grinberg, N., Tang, H. H., Huang, Q. Q., Teo, S. M., Ahola-Olli, A. V., et al. (2019). Multivariate Genome-wide Association Analysis of a Cytokine Network Reveals Variants with Widespread Immune, Haematological, and Cardiometabolic Pleiotropy.. American journal of human genetics, 105 (6), 1076-1090. https://doi.org/10.1016/j.ajhg.2019.10.001
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 underlie them, remain unknown. Here, we aimed to identify and characterise genetic variants with pleiotropic effects on cytokines. Using three population-based cohorts (N=9,263), we performed multivariate genome-wide association scans for a correlation network of 11 circulating cytokines, then combined our results in meta-analysis. We identified a total of 8 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 of publicly available GWAS summary statistics with the cytokine network associations using Bayesian colocalisation analysis, 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.
Humans, Cardiovascular Diseases, Genetic Predisposition to Disease, Blood Proteins, Cytokines, Prognosis, Longitudinal Studies, Follow-Up Studies, Prospective Studies, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome, Human, Adolescent, Adult, Aged, Middle Aged, Child, Female, Male, Gene Regulatory Networks, Genome-Wide Association Study, Young Adult, Genetic Pleiotropy, Biomarkers
Artika Nath was supported by an Australian Postgraduate Award. This research was supported in part by the Victorian Government’s OIS Program. Michael Inouye was supported by an NHMRC and Australian Heart Foundation Career Development Fellowship (no. 1061435). Gad Abraham was supported by an NHMRC Early Career Fellowship (no. 1090462). Qin Qin Huang is supported by the Melbourne International Research Scholarship. The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; and EU Horizon 2020 (grant 755320 for TAXINOMISIS); and European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation. Peter Würtz is supported by the Novo Nordisk Foundation (15998) and Academy of Finland (312476 and 312477).
Research Council of Norway (via University of Oslo) (275478)
WELLCOME TRUST (107881/Z/15/Z)
Medical Research Council (MC_UU_00002/4)
British Heart Foundation (RG/13/13/30194)
British Heart Foundation (RG/18/13/33946)
External DOI: https://doi.org/10.1016/j.ajhg.2019.10.001
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297489
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/