Association Analyses Identifies Psoriasis Insertion/Deletion Variants In Chinese Han Population

Background:Psoriasis is a common chronic inflammatory skin diseases, including four major types as psoriasis vulgaris, erythrodermic psoriasis, Psoriasis pustulose and psoriatic arthritis. The most common type is psoriasis vulgaris with the major clinical manifestations of erythema or patches covered with silver white scales which can occur on any part of the body. Psoriasis is one of the major diseases in dermatology and has been listed as a stubborn disease in the field of skin diseases in the 20th century by World Health Organization (WHO). According to some statistics, there are almost 80 million psoriasis patients worldwide. Psoriasis is easy to relapse and hard to cure. About 40% patients are accompanied by joint damage. There is no specific treatment yet. The disease seriously impair their physical and mental health. The incidence of psoriasis is diverse in different population and it is 0.123% in China. Many inducing factors have been reported, such as sun exposure, trauma and systemic drugs.The pathogenesis of psoriasis is not fully clarified yet. Studies have confirmed that it is a polygenic disease caused by both genetic and environment factors. Genetic epidemiology researches showed the prevalence of the first and second relatives of the probands is significantly increased compared with that in general population. Genome wide linkage analysis have identified 12 susceptibility regions in several different chromosomes. With the wide application of genome wide association study (GWAS), more and more susceptibility genes have been identified. Up to date, there are 8 GWASs in different populations have been included in GWAS Catalog database, while the Meta analysis further explored the susceptibility genes/loci. Recently, the genetic studies base on exome and targeted sequencing as well as exome chips plays an important role in finding the functional coding variants for psoriasis. Currently, there are 74 susceptibility genes/loci have been found with the application of GWAS, meta analysis, exome/targeted sequencing and exome chips which largely improve the knowledge of the genetic pathogenesis of psoriasis. However, almost all the discovered variants are SNPs which only explained a small part of the heritability of psoriasis. There are a large number of unknown genetic factors should be further explored.Insertion/deletion (Indel) is another large type of variants. Recent studies found that Indel was associated with many common and rare diseases. The Indel studies of psoriasis were only focus on a few genes, such as the angiotensin converting enzyme (ACE) gene. The systematically explore in the whole exome region is still lack.Objective:To systematically explore the associated Indels of psoriasis with a large scale samples using exome and targeted sequencing technology in Chinese Han population, clarify the role of the Indels in psoriasis and to analyse whether the identified Indels are independent signals for psoriasis.Methord:Exome sequencing was conducted in psoriasis patients and 676 healthy controls in Chinese Han population using Illumian Hiseq 2000 platform. The 1,326 candidate genes selected based on the single variant and gene based analysis in the sequencing data as well as previously reported immune disease related genes(including the psoriasis associated genes identified by GWAS) were studied using targeted sequencing. The Indels were summarized and categorized according to the 9 catalogues: exonic region, splice site, noncoding RNA,5’ untranslated region,3’untranslated region, intronic region, upstream,downstream and intergenic region. Association study was conducted based on the data of targeted sequencing using Plink software to systematically explore the associated Indels. The significant Indels were acquired after the correction of multiple test. Regression analysis was used to compare the significant Indels with the most significant SNPs in the same region to confirm whether the identified Indels were independent signals.Results:A total of 4,134 Indels were identified in targeted sequencing data. After annotation, the largest catalogue of Indels is located in the intronic region with a number of 3,530.Association analysis identified 26 Indels with P< 5×10-3 and 13 Indels are still significant after multiple test (P<10-6) which were located in ERAP1, UBLCP1, IFIH1, ZNF816A, STAT3, GJB2, LNPEP, GPLD1 and BRD3 genes. Two Indels are located in the exonic regions of ZNF816A and GJB2 genes. All the Indels were located in the regions in which the susceptibility loci have been reported except the Indel in BRD3 gene. The significance of associated Indels were disappeared after control the most significant SNPs in the same regions except the two Indels in the ZNF816A and GJB2 genes which implied these Indels are the same signals with the significant SNPs.Conclusion:The association between Indels and psoriasis was systematically explored using high throughput sequencing in Chinese Han population and several psoriasis associated Indels were identified. This study constructed the Indel variants database of psoriasis cases and controls in China and deepens the understanding of the pathogenesis of psoriasis. It provided the basis for subsequent functional studies and the lessons to systematically find the Indels of other diseases.