A transcriptome-wide association study identifies novel susceptibility genes for psoriasis

Abstract

Although more than 80 psoriasis genetic risk loci have been reported through genome-wide association studies (GWASs), the genetic mechanism of psoriasis remains unclear. To identify novel candidate genes associated with psoriasis and reveal the potential effects of genetic factors in the development of psoriasis, we conducted a transcriptome-wide association study (TWAS) based on summary statistics from GWAS of psoriasis (5175 cases and 447 089 controls) and gene expression levels from six tissues datasets (blood and skin). We identified 11 conditionally independent genes for psoriasis after Bonferroni corrections, such as the most significant genes UBLCP1 (PYFS = 2.98 × 10−16), and LCE3C (PSNSE = 9.72 × 10−12, PSSE = 6.24 × 10−12). The omnibus test identified additional 5 genes associated with psoriasis via the joint association model from multiple reference tissues. Among the 16 identified genes, 5 genes (CTSW, E1F1AD, KLRC3, FIBP, and EFEMP2) were regarded as novel genes for psoriasis. We evaluated the 16 candidate genes by querying public databases and identified 11 differentially expressed genes and 8 genes proved by the knockout mice models. Through GO enrichment analyses, we found that TWAS genes were enriched in the known GO terms associated with skin development, such as cornified envelope (P = 4.80 × 10−8) and peptide cross-linking (P = 1.50 × 10−7). Taken together, our results detected multiple novel candidate genes for psoriasis, providing clues for understanding the genetic mechanism of psoriasis.

A Transcriptome-Wide Analysis of Psoriasis: Identifying the Potential Causal Genes and Drug Candidates

“…We performed a tissue prioritization process using LDSC-SEG analysis using a multi-tissue RNA expression dataset and a multitissue chromatin modification dataset (Figure 2 and Supplementary Figure S1). Our tissue prioritization results led us to include additional relevant tissues (spleen, EBV-transformed lymphocytes, esophagus mucosa, and stomach) that were not used in the previous psoriasis TWAS study [63]. Previous studies have demonstrated that the spleen, lymphocytes, and gastrointestinal tract are associated with psoriasis [49,[64][65][66][67][68].…”

From Empirical to Pathogenesis-Based Treatments for Psoriasis

“…Psoriasis is a polygenic disease. More than 80 psoriasis risk loci have been reported (Zhu et al, 2021). Several of these genes are associated with the biological mechanisms as explained earlier.…”

Functional Genomics and Insights into the Pathogenesis and Treatment of Psoriasis

“…In this way, it is possible to determine the level to which all disease-associated variants within a locus contribute to differential gene expression, and is a powerful tool to relate risk genotype to function. Previous TWAS studies have uncovered novel putative psoriasis risk genes [35], with Jeong et al highlighting SSBP4 as significantly downregulated in psoriatic skin and fibroblasts [36]. SSBP4 increased transcription of interleukin 36 receptor agonist (IL36RA), IL-36RA reduces IL-36 activity, a cytokine has been found to stimulate IL-23 production and to have increased levels in psoriasis patients [37].…”