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

Abstract

BackgroundGenome-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.MethodsWe 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.ResultsHalf 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.ConclusionsThese 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.

Sebaceous Gland Atrophy in Psoriasis: An Explanation for Psoriatic Alopecia?

“…A criterion of 4-fold differential expression (overexpression in SH vs. NN skin, and reduced expression in PP vs. NN skin), was selected by inspection of the plots shown in Figure S1. The expression behavior of this SG signature gene set in PP vs. NN skin was subsequently correlated with those of signature sets derived for various skin-resident cell types and keratinocytes treated with various cytokines, as described previously (Swindell et al, 2013, Swindell, Sarkar, 2015, Swindell et al, 2014). Additional details are presented in the Supplementary Methods.…”

The EGF receptor ligand amphiregulin controls cell division via FoxM1

“…As a final step, a Benjamini-Hochberg p-value correction is applied to generated FDR-correct p-values, accounting for the fact that the analyses was repeated with respect to many different experiments. 78 …”

A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia

“…We identified 4 independent gene expression datasets from clinical trials in psoriasis using anti-TNF (etanercept; 2 independent datasets), anti-IL-23 (guselkumab), or anti-IL-17R (brodalumab) (48)(49)(50)(51). Consistent with the gene expression results in Figure 3, in these clinical trials, GRHL3 was significantly upregulated in lesional versus nonlesional skin, and after treatment, this high level was significantly reduced to levels similar to the nonlesional controls in all but 1 etanercept trial, which still showed the correct trend (Supplemental Figure 6, A-D).…”