TY - JOUR

T1 - Whole blood co-expression modules associate with metabolic traits and type 2 diabetes

T2 - an IMI-DIRECT study

AU - Gudmundsdottir, Valborg

AU - Pedersen, Helle Krogh

AU - Mazzoni, Gianluca

AU - Allin, Kristine H.

AU - Artati, Anna

AU - Beulens, Joline W.

AU - Banasik, Karina

AU - Brorsson, Caroline

AU - Cederberg, Henna

AU - Chabanova, Elizaveta

AU - De Masi, Federico

AU - Elders, Petra J.

AU - Forgie, Ian

AU - Giordano, Giuseppe N.

AU - Grallert, Harald

AU - Gupta, Ramneek

AU - Haid, Mark

AU - Hansen, Torben

AU - Hansen, Tue H.

AU - Hattersley, Andrew T.

AU - Heggie, Alison

AU - Hong, Mun-Gwan

AU - Jones, Angus G.

AU - Koivula, Robert

AU - Kokkola, Tarja

AU - Laakso, Markku

AU - Løngreen, Peter

AU - Mahajan, Anubha

AU - Mari, Andrea

AU - McDonald, Timothy J.

AU - McEvoy, Donna

AU - Musholt, Petra B.

AU - Pavo, Imre

AU - Prehn, Cornelia

AU - Ruetten, Hartmut

AU - Ridderstrale, Martin

AU - Rutters, Femke

AU - Sharma, Sapna

AU - Slieker, Roderick C.

AU - Syed, Ali

AU - Tajes, Juan Fernandez

AU - Thomas, Cecilia Engel

AU - Thomsen, Henrik S.

AU - Vangipurapu, Jagadish

AU - Vestergaard, Henrik

AU - Vinuela, Ana

AU - Wesolowska-Andersen, Agata

AU - Walker, Mark

AU - Adamski, Jerzy

AU - Schwenk, Jochen M.

AU - McCarthy, Mark

AU - Pearson, Ewan

AU - Dermitzakis, Emmanouil

AU - Franks, Paul W.

AU - Pedersen, Oluf

AU - Brunak, Søren

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Type 2 diabetes

KW - Transcriptomics

KW - Co-expression modules

KW - Omics data integration

KW - GENE-EXPRESSION PROFILES

KW - GENOME-WIDE ASSOCIATION

KW - INSULIN-RESISTANCE

KW - MONONUCLEAR-CELLS

KW - BIOMARKERS

KW - COUNT

KW - RISK

KW - TRANSCRIPTOME

KW - INFLAMMATION

KW - DRIVERS

U2 - 10.1186/s13073-020-00806-6

DO - 10.1186/s13073-020-00806-6

M3 - Journal article

C2 - 33261667

VL - 12

JO - Genome Medicine

JF - Genome Medicine

SN - 1756-994X

IS - 1

M1 - 109

ER -