Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study
Authors: Gudmundsdottir Valborg , Pedersen Helle Krogh , Mazzoni Gianluca , Allin Kristine H. , Artati Anna , Beulens Joline W. , Banasik Karina , Brorsson Caroline , Cederberg Henna , Chabanova Elizaveta , De Masi Federico , Elders Petra J. , Forgie Ian , Giordano Giuseppe N. , Grallert Harald , Gupta Ramneek , Haid Mark , Hansen Torben , Hansen Tue H. , Hattersley Andrew T. , Heggie Alison , Hong Mun-Gwan , Jones Angus G. , Koivula Robert , Kokkola Tarja , Laakso Markku , Løngreen Peter , Mahajan Anubha , Mari Andrea , McDonald Timothy J. , McEvoy Donna , Musholt Petra B. , Pavo Imre , Prehn Cornelia , Ruetten Hartmut , Ridderstråle Martin , Rutters Femke , Sharma Sapna , Slieker Roderick C. , Syed Ali , Tajes Juan Fernandez , Thomas Cecilia Engel , Thomsen Henrik S. , Vangipurapu Jagadish , Vestergaard Henrik , Viñuela Ana , Wesolowska-Andersen Agata , Walker Mark , Adamski Jerzy , Schwenk Jochen M. , McCarthy Mark I. , Pearson Ewan , Dermitzakis Emmanouil , Franks Paul W. , Pedersen Oluf , Brunak Søren 
Published: December 2020

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.