Integrative Analysis Of Genomic,transcriptomic And Epigenomic Data Reveals Regulatory Mechanisms Of Vitiligo

Background Vitiligo is a common acquired depigmentation disease in clinic.The main clinical manifestations are white patches,which can occur in different ages and genders.Skin lesions can occur in any part,especially in exposed parts and friction parts.The depigmentation of this disease is due to the gradual decrease and absence of melanocytes in the relevant areas.Because of its disfigurement,it seriously affects the quality of life of patients.There are many ways to treat vitiligo,and different individuals have different response to the treatment.Although some patients have certain self limitation,they are easy to relapse and delay.For the pathogenesis of vitiligo,recent studies have shown that genetic factors play a very important role in the occurrence and development of vitiligo.Previous studies on families or twins have shown that vitiligo has a strong genetic tendency.In addition,it also includes the autoimmune hypothesis,oxidative stress,melanocyte apoptosis,keratinocyte dysfunction and so on.The etiology of vitiligo is not clear.It is a multifactor disease involving genetic and environmental factors.Many factors may lead to the occurrence of the disease.The pathogenesis of vitiligo involves cell biology,neuroendocrinology,immunology and other fields.Many problems remain to be solved.In recent decades,many genetic studies have been used to determine the genetic factors of vitiligo,such as candidate gene analysis and linkage studies.In the past decade,the focus of genetic research on complex diseases has been focused on genome wide association studies(GWAS),which have been applied to vitiligo.About 100 genetic variations have been found according to the GWAS catalogue.In recent years,a large number of studies on the genetics of vitiligo have been published every year,including GWAS research,genome research,transcriptome research,epigenome and so on.They are determined to study and find the predisposing or pathogenic factors related to vitiligo from various perspectives,and carry out further research on its pathogenesis.In this study,we used the Mendelian randomization method,using genetic variation as a tool,to integrate the summary level data from GWAS,expression quantitative trait loci(e QTL)and methylation quantitative trait loci(me QTL)to analyze the function related genes and regulatory elements of vitiligo To further summarize the pathogenesis of vitiligo.Objective In this study,we use Mendelian randomization method and genetic variation as a tool to mine the possible biomarkers in the pathogenesis of vitiligo by integrating the data from GWAS,e QTL and me QTL,classify the regulatory genes,further summarize the main related pathways and regulatory pathways of vitiligo,and predict the future development of vitiligo.The effect of transcribed variants on the susceptibility of vitiligo may provide new insights into the mechanism of later research and treatment.Method This study integrated summary level data from GWAS,e QTL and me QTL to identify the functionally relevant genes of vitiligo and their regulatory elements.Our pipeline consists of three steps as follows: First,we integrate vitiligo GWAS and e QTL data to test for associations of gene expression with vitiligo.Next,we integrate vitiligo GWAS and me QTL data to test for association of DNAm with vitiligo.Last,we integrate e QTL data and me QTL data to test for associations between DNAm and their neighbouring genes(within 2Mb of each DNAm probe).If the association signals are significant in all three steps,then we predict with strong confidence that the identified DNAm sites are functionally relevant to the vitiligo through regulating the target genes.Results In this study,we detected 24 differentially methylated sites,of which 19 DNAm were hypomethylated and 5 DNAm were hypermethylated at a significance level for vitiligo.We also pinpointed a total of 20 vitiligo-associated genes,7 of them were not reported by previous GWAS.Conclusions our study that integrates genomic,transcriptomic and epigenomic information has identified number of vitiligo-associated genes and DNAm,which revealed a plausible regulatory mechanism that DNAm alter gene expression,and further causing disease.