Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study
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...
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| Format: | Article |
| Language: | English |
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BMC
2020-12-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-020-00806-6 |
| _version_ | 1818875123490357248 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Valborg Gudmundsdottir |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T13:21:30Z |
| format | Article |
| id | doaj.art-f4c2d5133478495aa5b959e30078db0a |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-19T13:21:30Z |
| publishDate | 2020-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-f4c2d5133478495aa5b959e30078db0a2022-12-21T20:19:42ZengBMCGenome Medicine1756-994X2020-12-0112111710.1186/s13073-020-00806-6Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT studyValborg Gudmundsdottir0Helle Krogh Pedersen1Gianluca Mazzoni2Kristine H. Allin3Anna Artati4Joline W. Beulens5Karina Banasik6Caroline Brorsson7Henna Cederberg8Elizaveta Chabanova9Federico De Masi10Petra J. Elders11Ian Forgie12Giuseppe N. Giordano13Harald Grallert14Ramneek Gupta15Mark Haid16Torben Hansen17Tue H. Hansen18Andrew T. Hattersley19Alison Heggie20Mun-Gwan Hong21Angus G. Jones22Robert Koivula23Tarja Kokkola24Markku Laakso25Peter Løngreen26Anubha Mahajan27Andrea Mari28Timothy J. McDonald29Donna McEvoy30Petra B. Musholt31Imre Pavo32Cornelia Prehn33Hartmut Ruetten34Martin Ridderstråle35Femke Rutters36Sapna Sharma37Roderick C. Slieker38Ali Syed39Juan Fernandez Tajes40Cecilia Engel Thomas41Henrik S. Thomsen42Jagadish Vangipurapu43Henrik Vestergaard44Ana Viñuela45Agata Wesolowska-Andersen46Mark Walker47Jerzy Adamski48Jochen M. Schwenk49Mark I. McCarthy50Ewan Pearson51Emmanouil Dermitzakis52Paul W. Franks53Oluf Pedersen54Søren Brunak55Department of Bio and Health Informatics, Technical University of DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Bio and Health Informatics, Technical University of DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of CopenhagenResearch Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental HealthAmsterdam UMC, location VUmc, Department of Epidemiology and Biostatistics, Amsterdam Public Health Research InstituteNovo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Bio and Health Informatics, Technical University of DenmarkDepartment of Endocrinology, Abdominal Center, Helsinki University HospitalDepartment of Diagnostic Radiology, Copenhagen University Hospital Herlev GentofteDepartment of Bio and Health Informatics, Technical University of DenmarkAmsterdam UMC, location VUmc, Department of General Practice, Amsterdam Public Health Research InstitutePopulation Health & Genomics, School of Medicine, University of Dundee, Ninewells HospitalGenetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, Skåne University HospitalGerman Center for Diabetes Research (DZD e.V.)Department of Bio and Health Informatics, Technical University of DenmarkResearch Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental HealthNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of CopenhagenNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of CopenhagenThe Institute of Clinical and Biological Sciences, University of Exeter College of Medicine and Health, University of ExeterInstitute of Cellular Medicine (Diabetes), Newcastle UniversityAffinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of TechnologyThe Institute of Clinical and Biological Sciences, University of Exeter College of Medicine and Health, University of ExeterGenetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, Skåne University HospitalInstitute of Clinical Medicine, Internal Medicine, University of Eastern FinlandInstitute of Clinical Medicine, Internal Medicine, University of Eastern FinlandDepartment of Bio and Health Informatics, Technical University of DenmarkWellcome Centre for Human Genetics, University of OxfordInstitute of Neurosciences, National Research CouncilNIHR Exeter Clinical Research Facility, University of Exeter Medical SchoolInstitute of Cellular Medicine (Diabetes), Newcastle UniversitySanofi, Diabetes Division, Research and DevelopmentEli Lilly Regional Operations GmbHResearch Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental HealthSanofi-Aventis Deutschland GmbH, R&DGenetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, Skåne University HospitalAmsterdam UMC, location VUmc, Department of Epidemiology and Biostatistics, Amsterdam Public Health Research InstituteGerman Center for Diabetes Research (DZD e.V.)Department of Cell and Chemical Biology, Leiden University Medical CenterDepartment of Bio and Health Informatics, Technical University of DenmarkWellcome Centre for Human Genetics, University of OxfordAffinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of TechnologyDepartment of Diagnostic Radiology, Copenhagen University Hospital Herlev GentofteInstitute of Clinical Medicine, Internal Medicine, University of Eastern FinlandNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Genetic Medicine and Development, University of Geneva Medical SchoolWellcome Centre for Human Genetics, University of OxfordInstitute of Cellular Medicine (Diabetes), Newcastle UniversityResearch Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental HealthAffinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of TechnologyOxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill HospitalPopulation Health & Genomics, School of Medicine, University of Dundee, Ninewells HospitalDepartment of Genetic Medicine and Development, University of Geneva Medical SchoolGenetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, Skåne University HospitalNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Bio and Health Informatics, Technical University of DenmarkAbstract 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.https://doi.org/10.1186/s13073-020-00806-6Type 2 diabetesTranscriptomicsCo-expression modulesOmics data integration |
| spellingShingle | 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 Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study Genome Medicine Type 2 diabetes Transcriptomics Co-expression modules Omics data integration |
| title | Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study |
| title_full | Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study |
| title_fullStr | Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study |
| title_full_unstemmed | Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study |
| title_short | Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study |
| title_sort | whole blood co expression modules associate with metabolic traits and type 2 diabetes an imi direct study |
| topic | Type 2 diabetes Transcriptomics Co-expression modules Omics data integration |
| url | https://doi.org/10.1186/s13073-020-00806-6 |
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