Multivariate Genome-wide Association Analysis of a Cytokine Network Reveals Variants with Widespread Immune, Haematological, and Cardiometabolic Pleiotropy

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Nath , A P , Ritchie , S C , Grinberg , N F , Tang , H H-F , Huang , Q Q , Teo , S M , Ahola-Olli , A V , Würtz , P , Havulinna , A S , Santalahti , K , Pitkanen , N , Lehtimäki , T , Kähönen , M , Lyytikäinen , L-P , Raitoharju , E , Seppälä , I , Sarin , A-P , Ripatti , S , Palotie , A , Perola , M , Viikari , J S , Jalkanen , S , Maksimow , M , Salmi , M , Wallace , C , Raitakari , O T , Salomaa , V , Abraham , G , Kettunen , J & Inouye , M 2019 , ' Multivariate Genome-wide Association Analysis of a Cytokine Network Reveals Variants with Widespread Immune, Haematological, and Cardiometabolic Pleiotropy ' , American Journal of Human Genetics , vol. 105 , no. 6 , pp. 1076-1090 . https://doi.org/10.1016/j.ajhg.2019.10.001

Title: Multivariate Genome-wide Association Analysis of a Cytokine Network Reveals Variants with Widespread Immune, Haematological, and Cardiometabolic Pleiotropy
Author: Nath, Artika P.; Ritchie, Scott C.; Grinberg, Nastasiya F.; Tang, Howard Ho-Fung; Huang, Qin Qin; Teo, Shu Mei; Ahola-Olli, Ari V.; Würtz, Peter; Havulinna, Aki S.; Santalahti, Kristiina; Pitkanen, Niina; Lehtimäki, Terho; Kähönen, Mika; Lyytikäinen, Leo-Pekka; Raitoharju, Emma; Seppälä, Ilkka; Sarin, Antti-Pekka; Ripatti, Samuli; Palotie, Aarno; Perola, Markus; Viikari, Jorma S.; Jalkanen, Sirpa; Maksimow, Mikael; Salmi, Marko; Wallace, Chris; Raitakari, Olli T.; Salomaa, Veikko; Abraham, Gad; Kettunen, Johannes; Inouye, Michael
Contributor organization: Institute for Molecular Medicine Finland
Genomics of Neurological and Neuropsychiatric Disorders
University of Helsinki
Diabetes and Obesity Research Program
Research Programs Unit
Staff Services
Complex Disease Genetics
Centre of Excellence in Complex Disease Genetics
Department of Public Health
Samuli Olli Ripatti / Principal Investigator
University Management
Biostatistics Helsinki
Aarno Palotie / Principal Investigator
Helsinki University Hospital Area
Date: 2019-12-05
Language: eng
Number of pages: 15
Belongs to series: American Journal of Human Genetics
ISSN: 0002-9297
DOI: https://doi.org/10.1016/j.ajhg.2019.10.001
URI: http://hdl.handle.net/10138/322379
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 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.
Subject: VON-WILLEBRAND-FACTOR
BLOOD-GROUP GENOTYPE
CARDIOVASCULAR RISK
GENETIC-VARIANTS
FACTOR-VIII
ABO
IL-1RA
METAANALYSIS
ANTAGONIST
EXPRESSION
1184 Genetics, developmental biology, physiology
Peer reviewed: Yes
Rights: unspecified
Usage restriction: openAccess
Self-archived version: publishedVersion


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