A Genome-wide Association Study For Coding Variants Of Psoriasis

Background Psoriasis is a chronic inflammatory hyperproliferative cutaneous disease with dynamic interactions between the immune system and the epidermis that affects up to 3% of the population worldwide. The prevalence of psoriasis varies by races, geographic location and period. Patients with psoriasis are increasing every year in China. The patients are suffering from the physical, social and psychological impact of this disease which reducesthe quality of life. Currently, the pathogenesis of psoriasis are not yet fully understood by people, abnormal production of inflammatory cytokinesis play a key role in the pathogenesis of psoriasis. Most scholars believe that psoriasis is a complex disease combination of genetic and environmental interactions. And genetic factors are major cause to psoriasis susceptibility. Furthermore, psoriasis is one of the complex polygenic diseases caused by a number of susceptibility genes. More than 74 susceptibility genes or loci have been identified for psoriasis in diverse populations, mostly through genome-wide association studies(GWASs). However, each of these identified genes or loci has a small or moderate effect, which only collectively explains a small proportion of the genetic variation in psoriasis. The “missing heritability” in psoriasis is evident. Furthermore, most of these previously identified variants are located in non-coding genomic regions and thus provide few clues as to the functional mechanism through which these variants affect the disease. Coding variants with high penetrance which were poorly covered in conventional GWASs may contribute to finding the “missing heritability” in complex disorders.Recent technological advances in high-throughput sequencing provide an opportunity to resequence multiple genetic regions and have generated compelling evidence that coding variants contribute to the mechanisms of psoriasis and other complex disorders. However, these efforts to investigate coding variants are still limited due to sample size and thus the statistical power. Studies using new exome chips show their ability to comprehensively identify coding variants for several complex traits.Objective This study aimed to systematically investigate the coding variants in psoriasis to the genetic susceptibility in a genome-wide scale and further identifiy low-frequency and rare variants association with the disease.Method Here, we perform the first exome-wide association study in large scale individuals(11,245 cases and 11,177 controls) to systematically investigate the coding variants in psoriasis by using Illumina Human Exome Asian Bead Chip(Exome_Asian Array) and Illumina Human Exome Fine Mapping Bead Chip(Exome_Fine Array). We performed a meta-analysis of the first two stages and selected the top 76 SNPs for further genotyping in an independent replication cohort of 6,369 cases and 13,969 controls.Result We discover 16 SNPs within 15 new genes/loci associated with psoriasis, including C1orf141, ZNF683, TMC6, AIM2, IL1RL1, CASR,SON, ZFYVE16, MTHFR, CCDC129, ZNF143, AP5B1, SYNE2, IFNGR2 and 3q26.2-q27(P<5.00 × 10-08). In addition, we also replicate 4 known susceptibility loci TNIP1, NFKBIA, IL12 B, and LCE3D-LCE3 E. These susceptibility variants identified in current study collectively account for 1.9% of the psoriasis heritability. The variant within AIM2 is predicted to impact protein structure.Conclusion This study was designed to maximise statistical power in a cost-effective manner by adopting a multi-stage analysis strategy for a large-scale Han Chinese population resulting in the identification of 15 new susceptibility genes/loci for psoriasis. Our findings highlight the genetic contributions of common coding variants to the pathogenesis of psoriasis and increase the number of known genetic risk factors for psoriasis.