Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.
Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.
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DOI：
10.1186/s13073-020-00806-6
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发表时间：
2020-12-01
期刊：
影响因子：
12.3
通讯作者：
Brunak S
中科院分区：
文献类型：
--
作者：
Gudmundsdottir V;Pedersen HK;Mazzoni G;Allin KH;Artati A;Beulens JW;Banasik K;Brorsson C;Cederberg H;Chabanova E;De Masi F;Elders PJ;Forgie I;Giordano GN;Grallert H;Gupta R;Haid M;Hansen T;Hansen TH;Hattersley AT;Heggie A;Hong MG;Jones AG;Koivula R;Kokkola T;Laakso M;Løngreen P;Mahajan A;Mari A;McDonald TJ;McEvoy D;Musholt PB;Pavo I;Prehn C;Ruetten H;Ridderstråle M;Rutters F;Sharma S;Slieker RC;Syed A;Tajes JF;Thomas CE;Thomsen HS;Vangipurapu J;Vestergaard H;Viñuela A;Wesolowska-Andersen A;Walker M;Adamski J;Schwenk JM;McCarthy MI;Pearson E;Dermitzakis E;Franks PW;Pedersen O;Brunak S
2型糖尿病（T2 D）患病率的上升构成了一个重大的全球挑战。代谢失调和T2 D的转录组特征在何种程度上可以在容易接近的组织如血液中观察到，这仍然是未解决的。此外，需要进行大规模的人体研究，以进一步了解胰岛素抵抗和T2 D的假定炎症成分。在这里，我们使用来自IMI-DIRECT队列的T2 D患者（n = 789）和非T2 D患者（n = 2127）的转录组学数据来描述全血的共表达结构，主要反映免疫系统的过程和细胞类型，以及它如何与代谢相关的临床特征和T2 D相关。在非糖尿病IMI-DIRECT队列中鉴定了共表达基因簇，并评价了稳定性以及T2 D个体队列中的保存和重新连接。我们进行了功能和免疫细胞签名富集分析，以及全基因组关联研究，以描述模块的遗传调控。在IMI-DIRECT两个队列中研究了转录组模块的表型和反式组学关联。我们鉴定了55个全血共表达模块，其中一些聚集在较大的超级模块中。我们确定了大量的协会之间的这些转录模块和措施的胰岛素作用和葡萄糖耐量。一些代谢相关模块反映血液中嗜中性粒细胞-淋巴细胞比率，而其他模块独立于白色血细胞估计值，包括编码具有抗菌特性的嗜中性粒细胞颗粒蛋白的基因模块，观察到其与临床特征和T2 D状态的最强关联。通过整合遗传和多组学数据，我们提供了一个整体的看法，调节和全血转录组模块的分子背景。我们还鉴定了T2 D的遗传信号与参与II型干扰素信号传导的共表达模块之间的重叠。我们的研究结果提供了代谢疾病背景下全血转录组模块的大规模图谱，并为未来与T2 D相关的研究提供了新的生物学候选物。
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. 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. 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. 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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影响因子：
14.9
作者：
Kamburov A;Stelzl U;Lehrach H;Herwig R
通讯作者：
Herwig R
影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
7.7
作者：
Floegel A;Stefan N;Yu Z;Mühlenbruch K;Drogan D;Joost HG;Fritsche A;Häring HU;Hrabě de Angelis M;Peters A;Roden M;Prehn C;Wang-Sattler R;Illig T;Schulze MB;Adamski J;Boeing H;Pischon T
通讯作者：
Pischon T
影响因子：
2.7
作者：
Evangelista AF;Collares CV;Xavier DJ;Macedo C;Manoel-Caetano FS;Rassi DM;Foss-Freitas MC;Foss MC;Sakamoto-Hojo ET;Nguyen C;Puthier D;Passos GA;Donadi EA
通讯作者：
Donadi EA