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

当前位置： X-MOL 学术 › Am. J. Hum. Genet. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Multivariate Genome-wide Association Analysis of a Cytokine Network Reveals Variants with Widespread Immune, Haematological, and Cardiometabolic Pleiotropy.
American Journal of Human Genetics ( IF 9.8 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.ajhg.2019.10.001
Artika P Nath ₁ , Scott C Ritchie ₂ , Nastasiya F Grinberg ₃ , Howard Ho-Fung Tang ₄ , Qin Qin Huang ₅ , Shu Mei Teo ₂ , Ari V Ahola-Olli ₆ , Peter Würtz ₇ , Aki S Havulinna ₈ , Kristiina Santalahti ₉ , Niina Pitkänen ₁₀ , Terho Lehtimäki ₁₁ , Mika Kähönen ₁₂ , Leo-Pekka Lyytikäinen ₁₁ , Emma Raitoharju ₁₁ , Ilkka Seppälä ₁₁ , Antti-Pekka Sarin ₈ , Samuli Ripatti ₁₃ , Aarno Palotie ₁₄ , Markus Perola ₈ , Jorma S Viikari ₁₅ , Sirpa Jalkanen ₉ , Mikael Maksimow ₉ , Marko Salmi ₁₆ , Chris Wallace ₁₇ , Olli T Raitakari ₁₈ , Veikko Salomaa ₉ , Gad Abraham ₁₉ , Johannes Kettunen ₂₀ , Michael Inouye ₂₁

Affiliation

Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom; Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom.
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, United Kingdom.
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Department of Clinical Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland.
Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki 00014, Finland; Nightingale Health Ltd., Helsinki 00300, Finland.
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland; National Institute of Health and Welfare, Helsinki 00271, Finland.
Medicity Research Laboratory, Department of Medical Microbiology and Immunology, University of Turku, Turku 20520, Finland.
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland.
Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland; Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland.
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland; Department of Public Health, University of Helsinki, Helsinki 00014, Finland; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Department of Medicine, University of Turku, Turku 20520, Finland; Division of Medicine, Turku University Hospital, Turku 20520, Finland.
Medicity Research Laboratory and Institute of Biomedicine, University of Turku, Turku 20520, Finland.
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, United Kingdom; MRC Biostatistics Unit, Institute of Public Health, Cambridge CB2 0SR, United Kingdom.
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland; The Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20520, Finland.
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom; Department of Clinical Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
Medicity Research Laboratory, Department of Medical Microbiology and Immunology, University of Turku, Turku 20520, Finland; Computational Medicine, Centre for Life Course Health Research, University of Oulu, Oulu 90014, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio 70211, Finland; Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom; Department of Clinical Pathology, University of Melbourne, Parkville, Victoria 3010, Australia; The Alan Turing Institute, London, United Kingdom.

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.

中文翻译：

细胞因子网络的多变量全基因组关联分析揭示了具有广泛免疫、血液学和心脏代谢多效性的变异。

细胞因子是免疫系统的重要调节成分，其异常水平与许多疾病状态有关。尽管越来越多的证据表明细胞因子协同作用，但细胞因子之间的许多生理相互作用以及它们共同的遗传结构仍然未知。在这里，我们旨在识别和表征对细胞因子具有多效性影响的遗传变异。使用三个基于人群的队列 (n = 9,263)，我们对 11 种循环细胞因子的相关网络进行了多变量全基因组关联研究 (GWAS)，然后将我们的结果结合到荟萃分析中。我们确定了总共八个与细胞因子网络显着相关的位点，其中两个（PDGFRB 和 ABO）以前没有被检测到。此外，条件分析揭示了三个已知细胞因子基因座的另外四个次级信号。通过使用贝叶斯共定位分析，将公开可用的 GWAS 汇总统计数据与细胞因子网络关联进行整合，揭示了八个细胞因子基因座和其他特征之间共有的因果变异；特别是，ABO、SERPINE2 和 ZFPM2 基因座的细胞因子网络变异体对免疫相关蛋白的产生、脂蛋白和脂质水平等代谢特征、血小板计数等血细胞相关特征和关于冠状动脉疾病和2型糖尿病等疾病特征。公开可用的 GWAS 汇总统计数据与细胞因子网络关联揭示了八个细胞因子基因座和其他特征之间的共同因果变异；特别是，ABO、SERPINE2 和 ZFPM2 基因座的细胞因子网络变异体对免疫相关蛋白的产生、脂蛋白和脂质水平等代谢特征、血小板计数等血细胞相关特征和关于冠状动脉疾病和2型糖尿病等疾病特征。公开可用的 GWAS 汇总统计数据与细胞因子网络关联揭示了八个细胞因子基因座和其他特征之间的共同因果变异；特别是，ABO、SERPINE2 和 ZFPM2 基因座的细胞因子网络变异体对免疫相关蛋白的产生、脂蛋白和脂质水平等代谢特征、血小板计数等血细胞相关特征和关于冠状动脉疾病和2型糖尿病等疾病特征。

更新日期：2019-11-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南

全部期刊列表>>