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Co-expression analysis reveals interpretable gene modules controlled by trans-acting genetic variants.

Liis Kolberg | Nurlan Kerimov | Hedi Peterson | Kaur Alasoo
eLife | 2020

Understanding the causal processes that contribute to disease onset and progression is essential for developing novel therapies. Although trans-acting expression quantitative trait loci (trans-eQTLs) can directly reveal cellular processes modulated by disease variants, detecting trans-eQTLs remains challenging due to their small effect sizes. Here, we analysed gene expression and genotype data from six blood cell types from 226 to 710 individuals. We used co-expression modules inferred from gene expression data with five methods as traits in trans-eQTL analysis to limit multiple testing and improve interpretability. In addition to replicating three established associations, we discovered a novel trans-eQTL near SLC39A8 regulating a module of metallothionein genes in LPS-stimulated monocytes. Interestingly, this effect was mediated by a transient cis-eQTL present only in early LPS response and lost before the trans effect appeared. Our analyses highlight how co-expression combined with functional enrichment analysis improves the identification and prioritisation of trans-eQTLs when applied to emerging cell-type-specific datasets.

Pubmed ID: 32880574

Associated grants

  • Agency: Eesti Teadusagentuur, International
    Id: PSG59
  • Agency: Eesti Teadusagentuur, International
    Id: MOBJD67
  • Agency: Horizon 2020 Framework Programme, International
    Id: 825775
  • Agency: Eesti Teadusagentuur, International
    Id: IUT34-4
  • Agency: Eesti Teadusagentuur, International
    Id: PSG415
  • Agency: European Regional Development Fund, International
    Id: EXCITE

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This is a list of tools and resources that we have found mentioned in this publication.


PLINK (tool)

RRID:SCR_001757

Open source whole genome association analysis toolset, designed to perform range of basic, large scale analyses in computationally efficient manner. Used for analysis of genotype/phenotype data. Through integration with gPLINK and Haploview, there is some support for subsequent visualization, annotation and storage of results. PLINK 1.9 is improved and second generation of the software.

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ArrayExpress (tool)

RRID:SCR_002964

International functional genomics data collection generated from microarray or next-generation sequencing (NGS) platforms. Repository of functional genomics data supporting publications. Provides genes expression data for reuse to the research community where they can be queried and downloaded. Integrated with the Gene Expression Atlas and the sequence databases at the European Bioinformatics Institute. Contains a subset of curated and re-annotated Archive data which can be queried for individual gene expression under different biological conditions across experiments. Data collected to MIAME and MINSEQE standards. Data are submitted by users or are imported directly from the NCBI Gene Expression Omnibus.

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Weighted Gene Co-expression Network Analysis (tool)

RRID:SCR_003302

Software R package for weighted correlation network analysis. WGCNA is also available as point-and-click application. Unfortunately this application is not maintained anymore. It is known to have compatibility problems with R-2.8.x and newer, and the methods it implements are not all state of the art.

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Bioconductor (tool)

RRID:SCR_006442

Software repository for R packages related to analysis and comprehension of high throughput genomic data. Uses separate set of commands for installation of packages. Software project based on R programming language that provides tools for analysis and comprehension of high throughput genomic data.

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PEER (tool)

RRID:SCR_009326

Software collection of Bayesian approaches to infer hidden determinants and their effects from gene expression profiles using factor analysis methods. Applications of PEER have * detected batch effects and experimental confounders * increased the number of expression QTL findings by threefold * allowed inference of intermediate cellular traits, such as transcription factor or pathway activations This project offers an efficient and versatile C++ implementation of the underlying algorithms with user-friendly interfaces to R and python.

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LIMMA (tool)

RRID:SCR_010943

Software package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.

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GenomeStudio (tool)

RRID:SCR_010973

Visualize and analyze data generated by all of Illumina''s platforms.

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KEGG (tool)

RRID:SCR_012773

Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.

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MatrixEQTL (tool)

RRID:SCR_025513

Software tool for ultra fast eQTL analysis via large matrix operations.

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