Co-expression analysis reveals interpretable gene modules controlled by trans-acting genetic variants
| العنوان: | Co-expression analysis reveals interpretable gene modules controlled by trans-acting genetic variants |
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| المؤلفون: | Kaur Alasoo, Liis Kolberg, Nurlan Kerimov, Hedi Peterson |
| المصدر: | eLife eLife, Vol 9 (2020) |
| بيانات النشر: | Cold Spring Harbor Laboratory, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Genotype, QH301-705.5, Science, Quantitative Trait Loci, Cis effect, Gene Expression, Locus (genetics), Genomics, Computational biology, Disease, Quantitative trait locus, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Humans, Gene Regulatory Networks, Biology (General), Transcription factor, Gene, 030304 developmental biology, matrix factoriation, 0303 health sciences, Blood Cells, General Immunology and Microbiology, General Neuroscience, Genetics and Genomics, General Medicine, Chromosomes and Gene Expression, co-expression, trans-eQTL, 030104 developmental biology, Multiple comparisons problem, Expression quantitative trait loci, Medicine, Trans-acting, 030217 neurology & neurosurgery, Research Article, Human |
| الوصف: | BackgroundDeveloping novel therapies for complex disease requires better understanding of the causal processes that contribute to disease onset and progression. Although trans-acting gene expression quantitative trait loci (trans-eQTLs) can be a powerful approach to directly reveal cellular processes modulated by disease variants, detecting trans-eQTLs remains challenging due to their small effect sizes and large number of genes tested. However, if a single trans-eQTL controls a group of co-regulated genes, then multiple testing burden can be greatly reduced by summarising gene expression at the level of co-expression modules prior to trans-eQTL analysis.ResultsWe analysed gene expression and genotype data from six blood cell types from 226 to 710 individuals. We inferred gene co-expression modules with five methods on the full dataset, as well as in each cell type separately. We detected a number of established co-expression module trans-eQTLs, such as the monocyte-specific associations at the IFNB1 and LYZ loci, as well as a platelet-specific ARHGEF3 locus associated with mean platelet volume. We also discovered a novel trans association near the SLC39A8 gene in LPS-stimulated monocytes. Here, we linked an early-response cis-eQTL of the SLC39A8 gene to a module of co-expressed metallothionein genes upregulated more than 20 hours later and used motif analysis to identify zinc-induced activation of the MTF1 transcription factor as a likely mediator of this effect.ConclusionsOur analysis provides a rare detailed characterisation of a trans-eQTL effect cascade from a proximal cis effect to the affected signalling pathway, transcription factor, and target genes. This highlights how co-expression analysis combined with functional enrichment analysis can greatly improve the identification and prioritisation of trans-eQTLs when applied to emerging cell-type specific datasets. |
| اللغة: | English |
| DOI: | 10.1101/2020.04.22.055335 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e31b87c08e444017d64a02bb5a15f0c7 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e31b87c08e444017d64a02bb5a15f0c7 |
| قاعدة البيانات: | OpenAIRE |
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