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Exome-wide rare loss-of-function variant enrichment study in 21,347 Han Chinese individuals identifies four new susceptibility genes for psoriasis [healthy controls]

ABSTRACT: Most psoriasis-related genes or loci identified through genome-wide association studies (GWASs) represent common clusters and are located in non-coding regions of the human genome, providing only limited evidence for the role of coding variants in psoriasis. Two exome-wide case-control genotyping data sets were obtained from our previous study. Quality control was established for each data set, and the remaining markers in each were annotated using ANNOVAR. Gene-based analysis was performed on the annotation results. A total of 250 and 35 genes in the Exome_Fine and Exome_Asian Array cohorts, respectively, exceeded the threshold (P < 4.43 × 10-6). Merged gene-based analysis was then conducted on the same set of SNPs from seven genes common to both arrays, and the chi-square test was used to confirm all gene-based results. Ultimately, four new susceptibility genes were identified: BBS7 (Pcombine = 1.38 × 10−29), GSTCD (Pcombine = 8.35 × 10−47), LIPK (Pcombine = 1.02 × 10−19) and PPP4R3B (Pcombine = 1.79 × 10−33). This study identified four new susceptibility genes for psoriasis through a gene-based method using rare variants, contributing to our understanding of the pathogenesis of psoriasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131670 | GEO | 2019/05/25

REPOSITORIES: GEO

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Project description:Psoriasis is a chronic inflammatory skin disease related to immune, whose complexity of molecular mechanisms is still not fully clear. RNA sequencing has been widely applied in various fields including biological medicine. According to the bioinformatics analysis of differential genes, biomarkers and drug targets have been discovered for the diagnosis and treatment of diseases. Besides, the pathological mechanisms of disease and functions of gene can be evaluated. In the present study, we report the application of RNA sequencing in skin tissues from psoriatic and healthy persons. By obtaining 2139 differential expressed genes (DEGs), 208 significantly differential GO terms and 44 significantly differential pathways were generated. We found that the functions of DEGs were mainly related to cell cycle, inflammatory, virus, immune response and metabolic process.The major pathways included cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, chemokine signaling pathway, cell cycle, metabolic pathways, ribosome, peroxisome, steroid biosynthesis and biosynthesis of unsaturated fatty acids. Furthermore, co-expression network was constructed to identify core genes and relations between genes. we considered genes with high values of degree and k-core difference in the co-expression network as core genes, such as IFNG, IL26, TLR3, PRKCQ, TLR4, CD274, CDK1 and IL17A. We chose CD274, an important immune checkpoint, to evaluate its regulatory mechanisms. Candidate genes related to CD274 were evaluated by the co-expression network analysis, and the relations between CD274 and candidate genes were validated in epidermal keratinocytes. Finally, IFNG and CDK1 inhibitor (indirubin) were found increasing the expression levels of CD274. In addition, indirubin was confirmed to attenuate mouse psoriasis-like skin lesion with the mechanisms related to CD274. In conclusion, this study provides us a comprehensive transcriptome analysis method on psoriasis to identify core genes and explore the important regulatory functions of genes.

Project description:Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an NF-kB activator within skin epidermis, account for PSORS2. Here we describe fifteen additional rare, missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. Keratinocytes were transfected with wildtype Cardsh or one of 16 Card14 mutations (17 total samples). The cells were collected and RNA extracted to determine the effect of these mutations compared to wildtype Card14. No replicates are included.

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Exome-wide rare loss-of-function variant enrichment study in 21,347 Han Chinese individuals identifies four new susceptibility genes for psoriasis [healthy controls]

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