Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era

BMC Medical Genomics

Johann E Gudjonsson¹  Andrew Johnston¹  James T Elder¹  John J Voorhees¹  Mrinal K Sarkar¹  Philip E Stuart¹  William R Swindell¹ 

[1] Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, MI 48109-2200, USA

关键词: Transcription factor;    TNFRSF9;    Neutrophil;    Microarray;    Keratinocyte;    GWAS;    Fibroblast;    AP-1;   

Others  :  797021
DOI  :  10.1186/1755-8794-7-27

 received in 2013-11-03, accepted in 2014-05-16,  发布年份 2014

【 摘 要 】

Background

Genome-scale studies of psoriasis have been used to identify genes of potential relevance to disease mechanisms. For many identified genes, however, the cell type mediating disease activity is uncertain, which has limited our ability to design gene functional studies based on genomic findings.

Methods

We identified differentially expressed genes (DEGs) with altered expression in psoriasis lesions (n = 216 patients), as well as candidate genes near susceptibility loci from psoriasis GWAS studies. These gene sets were characterized based upon their expression across 10 cell types present in psoriasis lesions. Susceptibility-associated variation at intergenic (non-coding) loci was evaluated to identify sites of allele-specific transcription factor binding.

Results

Half of DEGs showed highest expression in skin cells, although the dominant cell type differed between psoriasis-increased DEGs (keratinocytes, 35%) and psoriasis-decreased DEGs (fibroblasts, 33%). In contrast, psoriasis GWAS candidates tended to have highest expression in immune cells (71%), with a significant fraction showing maximal expression in neutrophils (24%, P < 0.001). By identifying candidate cell types for genes near susceptibility loci, we could identify and prioritize SNPs at which susceptibility variants are predicted to influence transcription factor binding. This led to the identification of potentially causal (non-coding) SNPs for which susceptibility variants influence binding of AP-1, NF-κB, IRF1, STAT3 and STAT4.

Conclusions

These findings underscore the role of innate immunity in psoriasis and highlight neutrophils as a cell type linked with pathogenetic mechanisms. Assignment of candidate cell types to genes emerging from GWAS studies provides a first step towards functional analysis, and we have proposed an approach for generating hypotheses to explain GWAS hits at intergenic loci.

【 授权许可】

   
2014 Swindell et al.; licensee BioMed Central Ltd.

【 图 表 】

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