TY - JOUR
T1 - Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era
AU - Swindell, William R.
AU - Stuart, Philip E.
AU - Sarkar, Mrinal K.
AU - Voorhees, John J.
AU - Elder, James T.
AU - Johnston, Andrew
AU - Gudjonsson, Johann E.
N1 - Funding Information:
This work was supported by NIH grants AR042742 (JTE), AR050511 (JTE), AR062382 (JTE), AR065183 (JTE), AR054966 (JTE) and AR060802 (JEG). Additional support was provided by the Babcock Endowment Fund (AJ), Dermatology Foundation (AJ), American Skin Association (AJ and WRS), the A. Alfred Taubman Medical Research Institute Kenneth and Frances Eisenberg Emerging Scholar Award (JEG), and the Doris Duke Foundation (JEG). JTE is supported by the Ann Arbor VA Hospital. WRS is funded in part by the American Skin Association Carson Family Research Scholar Award in Psoriasis.
PY - 2014/5/22
Y1 - 2014/5/22
N2 - 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.
AB - 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.
KW - AP-1
KW - Fibroblast
KW - GWAS
KW - Keratinocyte
KW - Microarray
KW - Neutrophil
KW - TNFRSF9
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=84903625805&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903625805&partnerID=8YFLogxK
U2 - 10.1186/1755-8794-7-27
DO - 10.1186/1755-8794-7-27
M3 - Article
C2 - 24885462
AN - SCOPUS:84903625805
SN - 1755-8794
VL - 7
JO - BMC Medical Genomics
JF - BMC Medical Genomics
IS - 1
M1 - 27
ER -