Multivariate genome-wide association analysis of a cytokine network reveals variants with widespread immune, haematological and cardiometabolic pleiotropy

Artika P. Nath; Scott C. Ritchie; Nastasiya F. Grinberg; Howard H.F. Tang; Qin Huang; Shu Mei Teo; Ari Ahola‐Olli; Peter Würtz; Aki Samuli Havulinna; Kristiina Santalahti; Niina Pitkänen; Terho J. Lehtimäki; Mika A. P. Kähönen; Leo‐Pekka Lyytikäinen; Emma Raitoharju; Ilkka Seppälä; Antti‐Pekka Sarin; Samuli Ripatti; Aarno V. Palotie; Markus Perola; Jorma S.A. Viikari; Sirpa Jalkanen; Mikael Maksimow; Marko Salmi; Chris Wallace; Olli Tuomas Raitakari; Veikko V Salomaa; Gad Abraham; Johannes Kettunen; Michael Inouye

doi:10.1016/j.ajhg.2019.10.001

GenomicsThe American Journal of Human GeneticsOct 31, 2019

Peer-reviewed journal article

Multivariate genome-wide association analysis of a cytokine network reveals variants with widespread immune, haematological and cardiometabolic pleiotropy

Artika P. Nath iD, Scott C. Ritchie iD, Nastasiya F. Grinberg iD, Howard H.F. Tang iD, Qin Huang iD, Shu Mei Teo iD, Ari Ahola‐Olli iD, Peter Würtz iD, Aki Samuli Havulinna iD, Kristiina Santalahti iD, Niina Pitkänen iD, Terho J. Lehtimäki iD, Mika A. P. Kähönen iD, Leo‐Pekka Lyytikäinen iD, Emma Raitoharju iD, Ilkka Seppälä iD, Antti‐Pekka Sarin iD, Samuli Ripatti iD, Aarno V. Palotie iD, Markus Perola iD, Jorma S.A. Viikari iD, Sirpa Jalkanen iD, Mikael Maksimow iD, Marko Salmi iD, Chris Wallace iD, , Michael Inouye iD

Abstract

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 - to do this we performed a multivariate genome-wide association study on a correlation network of 11 circulating cytokines measured in 9,263 individuals. Meta-analysis identified a total of 8 loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. 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.

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