Abstract
BackgroundPsoriasis is an immune-mediated, inflammatory disorder of the skin characterized by chronic inflammation and hyperproliferation of the epidermis. Differential expression analysis of microarray or RNA-seq data have shown that thousands of coding and non-coding genes are differentially expressed between psoriatic and healthy control skin. However, differential expression analysis may fail to detect perturbations in gene coexpression networks. Sensitive detection of such networks may provide additional insight into important disease-associated pathways. In this study, we applied weighted gene coexpression network analysis (WGCNA) on RNA-seq data from psoriasis patients and healthy controls.ResultsRNA-seq was performed on skin samples from 18 psoriasis patients (pre-treatment and post-treatment with the TNF-α inhibitor adalimumab) and 16 healthy controls, generating an average of 52.3 million 100-bp paired-end reads per sample. Using WGCNA, we identified 3 network modules that were significantly correlated with psoriasis and 6 network modules significantly correlated with biologic treatment, with only 16 % of the psoriasis-associated and 5 % of the treatment-associated coexpressed genes being identified by differential expression analysis. In a majority of these correlated modules, more than 50 % of coexpressed genes were long non-coding RNAs (lncRNA). Enrichment analysis of these correlated modules revealed that short-chain fatty acid metabolism and olfactory signaling are amongst the top pathways enriched for in modules associated with psoriasis, while regulation of leukocyte mediated cytotoxicity and regulation of cell killing are amongst the top pathways enriched for in modules associated with biologic treatment. A putative autoantigen, LL37, was coexpressed in the module most correlated with psoriasis.ConclusionsThis study has identified several networks of coding and non-coding genes associated with psoriasis and biologic drug treatment, including networks enriched for short-chain fatty acid metabolism and olfactory receptor activity, pathways that were not previously identified through differential expression analysis and may be dysregulated in psoriatic skin. As these networks are comprised mostly of non-coding genes, it is likely that non-coding genes play critical roles in the regulation of pathways involved in the pathogenesis of psoriasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3188-y) contains supplementary material, which is available to authorized users.
Highlights
Psoriasis is an immune-mediated, inflammatory disorder of the skin characterized by chronic inflammation and hyperproliferation of the epidermis
Traditional differential expression analysis in PPvNN revealed that 5328 genes were differentially expressed (FDR ≤ 0.05), including 4357 coding genes and 971 long non-coding RNAs (lncRNA) (Additional file 1)
A validation of the DE lncRNAs was performed by implementing reverse transcriptase quantitative polymerase chain reaction (qPCR) on lncRNAs from 17 cases and 14 healthy controls
Summary
Psoriasis is an immune-mediated, inflammatory disorder of the skin characterized by chronic inflammation and hyperproliferation of the epidermis. Weighted gene coexpression network analysis (WGCNA) [9] builds upon these previous unweighted methods by implementing a correlation-based soft-thresholding weight that prioritizes the strongest pairwise correlations and penalizes weaker ones and complements differential expression analysis by testing for association between a disease and networks of correlated genes. Unlike methods such as Gene Set Enrichment Analysis [10], the WGCNA framework is based on the rationale that gene networks can be constructed with gene correlation matrices alone, without prior network or pathway information that can introduce bias. WGCNA has been successfully applied in screening for disease-associated pathways, molecular targets, and candidate genes in chronic fatigue syndrome [12], Sjögren’s Syndrome [13], coronary heart disease [14], and inflammatory bowel disease [15]
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