Meta-analysis Of Genome-wide Association Studies Identifies Susceptibility Genes Of Psoriasis In Chinese Population

Background Psoriasis is a disease caused by genetic,environmental and other factors.Genetic factors play an important role in the pathogenesis of psoriasis.The results of epidemiological investigation on twins also show that the incidence of psoriasis is very hereditary,and the susceptibility genes of psoriasis have population heterogeneity.Quantitative studies show that European and Chinese populations have their own unique susceptibility genes.With the application of various sequencing and analysis methods,more than 100 susceptibility genes associated with psoriasis have been found,but these previous susceptibility genes can only explain the genetic mechanism of partial disease groups.there are many susceptibility genes waiting for follow-up exploration and discovery.Therefore,researchers think of Meta-analysis.In order to improve the effectiveness of testing data,we can integrate multiple research results of the same category and independent of each other,supplement their accessibility,and make the sample size more compact,which is more conducive to the discovery of new benchmark data.In the process of exploring psoriasis susceptibility genes,many studies at home and abroad have shown that post-interpolation Meta-analysis of multiple psoriasis GWAS data can expand the sample size,find new susceptibility genes and supplement the genetic explanation of the disease.However,most of the meta-analyses were conducted by foreign teams or domestic and foreign multi-platform collaborations,and there are few studies on multi-platform meta-analyses of large samples of psoriasis susceptibility genes in Chinese population alone.Objective In this study,all samples were from the Chinese population.Meta-analysis was conducted based on our previous independent genotyping data,so as to search for new susceptibility genes and verify the found susceptibility genes for psoriasis.In addition,the function of the newly discovered genes was analyzed to provide reference for subsequent functional studies,provide a reliable basis for the construction of the Chinese population psoriasis susceptibility gene database,and supplement the genetic interpretation of the existing susceptibility genes for the disease.Methods A total of 45836 samples(19349 psoriasis cases and 26487 controls)were collected from the GWAS data of five Chinese genotyping platforms.Use thepan Asia database as the reference panel,after imputation,Plink-meta-analysis software selected as a tool to analyze the GWAS data of the five platforms after strict quality control.Compared with previously reported results of psoriasis GWAS,a preliminary discovery of candidate single nucleotide polymorphisms(SNP)associated with psoriasis.After functional annotation,SNPs were mapped to genes based on SNP location,expression quantitative trait Loci(EQTL),and chromatin interaction.Based on the results of GWAS,a set of prioritized genes were generated using the above three mapping methods,and then gene and gene enrichment analysis was performed using MAGMA on the FUMA platform.The Main histocompatibility complex(MHC)region was excluded by MAGMA,and the Linkage disequilibrium(LD)among the combined markers was analyzed by multiple regression,and the multi-marker effect was found.For gene analysis,the statistical information of SNPs in the whole gene is combined to detect the association between all SNPs within the whole gene and the disease.In gene enrichment analysis,genes with the same biological function were grouped and their association with disease was evaluated.Results Meta-analysis was performed after imputation of 5 independent Chinese psoriasis microarray data.Using FUMA GWAS as a tool to deal with the results of the meta-analysis,10 new loci were discovered and 16 new susceptibility genes were defined(TERT、PPARD、VANGL2、CXCR2、NPHP3、GRHL2、FKBP5、IL21、RUFY4、BBS12、TULP1、TEAD3、SSR1、CAGE1、EEPD1、PDHX).In addition,we further conducted gene enrichment analysis to investigate the metabolic pathways involved in the newly identified genes,and found that most of these genes are potentially associated with psoriasis.TERT and PPARD together participate in the negative regulation of cell proliferation.VANGL2,CXCR2,NPHP3,GRHL2,and PPARD are all involved in the growth pathway of epidermal cells;PPARD and FKBP5 are jointly involved in the pathway of response to biostimulation and bacterial response;CXCR2: IL21 is jointly involved in the signal pathway mediated by cytokines;CXCR2:IL21:RUFY4 participates in the cytokine response pathway;CXCR2:IL21:PPARD also participates in the immunerelated pathway;NPHP3:BBS12:TULP1 participates in the photoreceptor cell maintenance pathway;TEAD3 participates in the RUNX3 regulation of YAP1 mediated transcription pathway;IL21 participates in the JAK STA T signaling pathway.Four genes in three loci are not enriched in any metabolic pathways.They are the SSR1 and CAGE1 genes in chr6:7331682-7331682;the EEPD1 gene in chr7:36249621-36261744 and the PDHX gene in chr11:35036723-35069043..Among the 277 SNPs reported in China and other countries,139 SNPs were verified,the host genes of 121 SNPs were verified,But,17 loci,spread across six genes,could not be identified.The six genes were ADRA1 B,LOC401895,GPR85,PAK6,CAMK2 G,and UBAC2/RN7SKP9.Only one gene,ADRA1 B,has been reported in the Chinese population,while the others have been reported in European populations.Subsequently,a population heterogeneity analysis was carried out,which proved that the psoriasis susceptibility gene has population heterogeneity once again.Conclusion In this study,10 new loci were found,which supplemented the genetic explanations of the existing psoriasis susceptibility genes.Among the reported psoriasis SNPs,more than 90% loci or their genes were successfully verified,which fully demonstrated the credibility of the results of this study.After analyzing the correlation between the newly discovered gene function and the disease,the correlation between the new gene and psoriasis was confirmed,which provided a direction for future functional experiments and provided a reliable database for constructing a psoriasis susceptibility gene database in the Chinese population.