Genome Medicine (Dec 2020)
Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study
- Valborg Gudmundsdottir,
- Helle Krogh Pedersen,
- Gianluca Mazzoni,
- Kristine H. Allin,
- Anna Artati,
- Joline W. Beulens,
- Karina Banasik,
- Caroline Brorsson,
- Henna Cederberg,
- Elizaveta Chabanova,
- Federico De Masi,
- Petra J. Elders,
- Ian Forgie,
- Giuseppe N. Giordano,
- Harald Grallert,
- Ramneek Gupta,
- Mark Haid,
- Torben Hansen,
- Tue H. Hansen,
- Andrew T. Hattersley,
- Alison Heggie,
- Mun-Gwan Hong,
- Angus G. Jones,
- Robert Koivula,
- Tarja Kokkola,
- Markku Laakso,
- Peter Løngreen,
- Anubha Mahajan,
- Andrea Mari,
- Timothy J. McDonald,
- Donna McEvoy,
- Petra B. Musholt,
- Imre Pavo,
- Cornelia Prehn,
- Hartmut Ruetten,
- Martin Ridderstråle,
- Femke Rutters,
- Sapna Sharma,
- Roderick C. Slieker,
- Ali Syed,
- Juan Fernandez Tajes,
- Cecilia Engel Thomas,
- Henrik S. Thomsen,
- Jagadish Vangipurapu,
- Henrik Vestergaard,
- Ana Viñuela,
- Agata Wesolowska-Andersen,
- Mark Walker,
- Jerzy Adamski,
- Jochen M. Schwenk,
- Mark I. McCarthy,
- Ewan Pearson,
- Emmanouil Dermitzakis,
- Paul W. Franks,
- Oluf Pedersen,
- Søren Brunak
Affiliations
- Valborg Gudmundsdottir
- Department of Bio and Health Informatics, Technical University of Denmark
- Helle Krogh Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Gianluca Mazzoni
- Department of Bio and Health Informatics, Technical University of Denmark
- Kristine H. Allin
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Anna Artati
- Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health
- Joline W. Beulens
- Amsterdam UMC, location VUmc, Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute
- Karina Banasik
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Caroline Brorsson
- Department of Bio and Health Informatics, Technical University of Denmark
- Henna Cederberg
- Department of Endocrinology, Abdominal Center, Helsinki University Hospital
- Elizaveta Chabanova
- Department of Diagnostic Radiology, Copenhagen University Hospital Herlev Gentofte
- Federico De Masi
- Department of Bio and Health Informatics, Technical University of Denmark
- Petra J. Elders
- Amsterdam UMC, location VUmc, Department of General Practice, Amsterdam Public Health Research Institute
- Ian Forgie
- Population Health & Genomics, School of Medicine, University of Dundee, Ninewells Hospital
- Giuseppe N. Giordano
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, Skåne University Hospital
- Harald Grallert
- German Center for Diabetes Research (DZD e.V.)
- Ramneek Gupta
- Department of Bio and Health Informatics, Technical University of Denmark
- Mark Haid
- Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health
- Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Tue H. Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Andrew T. Hattersley
- The Institute of Clinical and Biological Sciences, University of Exeter College of Medicine and Health, University of Exeter
- Alison Heggie
- Institute of Cellular Medicine (Diabetes), Newcastle University
- Mun-Gwan Hong
- Affinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology
- Angus G. Jones
- The Institute of Clinical and Biological Sciences, University of Exeter College of Medicine and Health, University of Exeter
- Robert Koivula
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, Skåne University Hospital
- Tarja Kokkola
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland
- Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland
- Peter Løngreen
- Department of Bio and Health Informatics, Technical University of Denmark
- Anubha Mahajan
- Wellcome Centre for Human Genetics, University of Oxford
- Andrea Mari
- Institute of Neurosciences, National Research Council
- Timothy J. McDonald
- NIHR Exeter Clinical Research Facility, University of Exeter Medical School
- Donna McEvoy
- Institute of Cellular Medicine (Diabetes), Newcastle University
- Petra B. Musholt
- Sanofi, Diabetes Division, Research and Development
- Imre Pavo
- Eli Lilly Regional Operations GmbH
- Cornelia Prehn
- Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health
- Hartmut Ruetten
- Sanofi-Aventis Deutschland GmbH, R&D
- Martin Ridderstråle
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, Skåne University Hospital
- Femke Rutters
- Amsterdam UMC, location VUmc, Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute
- Sapna Sharma
- German Center for Diabetes Research (DZD e.V.)
- Roderick C. Slieker
- Department of Cell and Chemical Biology, Leiden University Medical Center
- Ali Syed
- Department of Bio and Health Informatics, Technical University of Denmark
- Juan Fernandez Tajes
- Wellcome Centre for Human Genetics, University of Oxford
- Cecilia Engel Thomas
- Affinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology
- Henrik S. Thomsen
- Department of Diagnostic Radiology, Copenhagen University Hospital Herlev Gentofte
- Jagadish Vangipurapu
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland
- Henrik Vestergaard
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Ana Viñuela
- Department of Genetic Medicine and Development, University of Geneva Medical School
- Agata Wesolowska-Andersen
- Wellcome Centre for Human Genetics, University of Oxford
- Mark Walker
- Institute of Cellular Medicine (Diabetes), Newcastle University
- Jerzy Adamski
- Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health
- Jochen M. Schwenk
- Affinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology
- Mark I. McCarthy
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital
- Ewan Pearson
- Population Health & Genomics, School of Medicine, University of Dundee, Ninewells Hospital
- Emmanouil Dermitzakis
- Department of Genetic Medicine and Development, University of Geneva Medical School
- Paul W. Franks
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, Skåne University Hospital
- Oluf Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Søren Brunak
- Department of Bio and Health Informatics, Technical University of Denmark
- DOI
- https://doi.org/10.1186/s13073-020-00806-6
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 17
Abstract
Abstract Background The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D. Methods Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts. Results We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling. Conclusions Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.
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