Three New Psoriasis Susceptibility Loci Were Identified By Exome Sequencing In Han Chinese Population

Background Psoriasis is a chronic and multifactorial skin diseasecharacterized by sharply demarcated erythematous plaques with adherentsilvery scales. Currently, the etiology and pathogenesis of psoriasis arenot fully understood, abnormal production of inflammatory mediators playan important role in the pathogenesis of this disease. Most scholars believethat psoriasis is the result of genetic and environmental interactions,and genetic factors are essential to psoriasis risk. Furthermore, psoriasisis one of the complex diseases caused by a number of common susceptibilitygene. The prevalence of psoriasis varies between different ethnic andgeographical populations, and ethnicity, geographic location, environmentand other factors are relative to the difference. Overall, the prevalenceof the Caucasian population is about2-3%, while low rate is observed inJapanese with the majority of patients with psoriasis are sporadic. In China,the prevalence of psoriasis is approximately0.123%with the total numberof patients close to10million, the distribution trends showed that theprevalence of male is higher than that of women, the prevalence in northand urban areas is higher than that in south and raral areas. Data for1043patients with psoriasis vulgaris suggests that the prevalence of psoriasisin first-and second-degree relatives of the proband with psoriasis was higher than that in the general population and the heritability of psoriasisin first-and second-degree relatives was67.04and46.59%, respectively.With the development of genetics research technologies and research methods,great progress have been made and a number of valuable diseasesusceptibility genes/regions have been identified."Positional cloning"and "positional candidate cloning" approachs are important methods usedto evaluate the genetic basis of Mendelian diseases and identify the causalgenes. In the end of last century, the genetic linkage analysis methodswere applied to the genetic susceptibility research of psoriasis. So far,10susceptibility loci were identified via the use of positional cloningand genome-wide linkage analysis, such as1q21,1p,3q21,4q,4q31-q34,6p21.33,16q,17q25,18p11.23and19p13. With the rapid development oftechnologies and genotyping costs continue to decrease, high-throughputcommercial SNP detection chip appears and constantly update, which makesgenome-wide association studies （GWAS） to develop. Currently, more than40susceptibility genes/loci have been identified through large-scaleassociation studies, particularly GWAS; however, most of the identifiedrisk variants are expected to be tagging SNPs, and the functional codingvariants of these susceptibility genes, particularly those that are of lowfrequency and rare, are largely refractory to the interrogation by GWASand have therefore not been systematically investigated. Objective This study aimed to investigate the contribution of functionalcoding variants and noncoding variants to the genetic susceptibility ofpsoriasis and identifiy additional association with the disease.Method We carried out a large-scale sequencing analysis of functionalcoding variants in two independent samples comprising21,309individualsof Chinese Han. First, we analyzed whole genome nonsynonymoussingle-nucleotide variants （SNVs） by exome sequencing in781cases and676controls, and following validation on1,326candidate genes by targetedsequencing in9,946cases and9,906controls of Chinese population. Forthe noncoding SNVs, we performed in-depth data analysis and a replicationstudy for22SNVs in an independent cohort of Chinese Han consisting of4,480cases and6,521controls based on the large-scale sequencing data（10,727cases and10,582controls） to find additional association with thedisease.Result For the nonsynonymous SNVs, we discovered6common and low frequencymissense SNVs that showed consistent association in the two independentsamples of exome and targeted sequencing analyses and achieved genome-widesignificance in combined analysis: chr1:67421184（c.G530A） at IL23R(P_exome-target=1.94×10^-11, OR=0.72), rs72474224（c.G324A） at GJB2(P_exome-target=7.46×10^-11, OR=1.34), rs512208（c.C185A） at LCE3D (P_exome-target=2.92×10^-23, OR=1.24), rs27044（c.C2535G） and rs26653（c.G727C） at ERAP1(P_exome-target =2.16×10^-14, OR=0.86and P_exome-target=5.27×10^-12, OR=0.87), and rs12459008（c.T590A） at ZNF816A (P_exome-target=2.25×10^-9, OR=0.88). One common missenseSNV rs1047781（c.A418T） and two rare missense SNVs （chr19:53898296/c.C271Tand chr19:53898541/c.C516G） in FUT2were also identified with suggestiveassociation evidence (P_exome-target=2.78×10^-6, OR=1.10, P_exome-target=5.51×10-5, OR=3.61and P_exome-target=2.92×10-3, OR=6.92, respectively). Forthe noncoding SNVs, we confirmed4previously reported psoriasissusceptibility genes: IL12B (rs2288831, P_exome-target=2.30×10-20, OR=0.83), IFIH1(rs13431841, P_exome-target=2.96×10^-09, OR=0.83), ERAP1(rs27043, P_exome-target=6.50×10^-12, OR=0.87) and RNF114(rs4647954, Pcombined=2.41×10^-07, OR=1.09),and identified3new susceptibility loci exceeded the genome-widesignificance threshold: NFKB1(rs1020760, P08exome-target=2.19×10-, OR=1.12;rs1609798, P_exome-target=9.87×10^-08, OR=1.12),12p13.3(rs758739, Pcombined=4.08×10^-08, OR=0.91; rs2243750, P08combined=4.38×10-, OR=0.91) and17q12(rs10852936, Pcombined=1.96×10^-08, OR=1.10, rs12936231, Pcombined=5.02×10^-08,OR=1.10). We also identified2additional loci exhibiting suggestiveevidence of an association:3p21.31（rs1863837, P7combined=3.91×10-0, OR=0.90） and17q25（rs3744017, P-07combined=5.83×10, OR=1.12）.Conclusion The results of this study indicated that coding variants, atleast nonsynonymous ones with low and rare frequency might have limitedcontribution to the overall genetic risk of psoriasis and increase thenumber of confirmed psoriasis risk loci.