Changbing Shen

Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease

The human major histocompatibility complex (MHC) region has been shown to be associated with numerous diseases. However, it remains a challenge to pinpoint the causal variants for these associations because of the extreme complexity of the region. We thus sequenced the entire 5-Mb MHC region in 20,635 individuals of Han Chinese ancestry (10,689 controls and 9,946 patients with psoriasis) and constructed a Han-MHC database that includes both variants and HLA gene typing results of high accuracy. We further identified multiple independent new susceptibility loci in HLA-C, HLA-B, HLA-DPB1 and BTNL2 and an intergenic variant, rs118179173, associated with psoriasis and confirmed the well-established risk allele HLA-C*06:02. We anticipate that our Han-MHC reference panel built by deep sequencing of a large number of samples will serve as a useful tool for investigating the role of the MHC region in a variety of diseases and thus advance understanding of the pathogenesis of these disorders.

Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis

Genome-wide association studies (GWASs) have reproducibly associated ∼40 susceptibility loci with psoriasis. However, the missing heritability is evident and the contributions of coding variants have not yet been systematically evaluated. Here, we present a large-scale whole-exome array analysis for psoriasis consisting of 42,760 individuals. 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 four known susceptibility loci TNIP1, NFKBIA, IL12B and LCE3D–LCE3E. These susceptibility variants identified in the current study collectively account for 1.9% of the psoriasis heritability. The variant within AIM2 is predicted to impact protein structure. Our findings increase the number of genetic risk factors for psoriasis and highlight new and plausible biological pathways in psoriasis.

Sequencing-based approach identified three new susceptibility loci for psoriasis

In a previous large-scale exome sequencing analysis for psoriasis, we discovered seven common and low-frequency missense variants within six genes with genome-wide significance. Here we describe an in-depth analysis of noncoding variants based on sequencing data (10,727 cases and 10,582 controls) with replication in an independent cohort of Han Chinese individuals consisting of 4,480 cases and 6,521 controls to identify additional psoriasis susceptibility loci. We confirmed four known psoriasis susceptibility loci (IL12B, IFIH1, ERAP1 and RNF114; 2.30 × 10(-20)≤P≤2.41 × 10(-7)) and identified three new susceptibility loci: 4q24 (NFKB1) at rs1020760 (P=2.19 × 10(-8)), 12p13.3 (CD27-LAG3) at rs758739 (P=4.08 × 10(-8)) and 17q12 (IKZF3) at rs10852936 (P=1.96 × 10(-8)). Two suggestive loci, 3p21.31 and 17q25, are also identified with P<1.00 × 10(-6). The results of this study increase the number of confirmed psoriasis risk loci and provide novel insight into the pathogenesis of psoriasis.

Epigenome-Wide Association Analysis Identified Nine Skin DNA Methylation Loci for Psoriasis

Psoriasis is a chronic hyperproliferative and inflammatory skin disease caused by the interplay of genetic and environmental factors. DNA methylation has been linked to psoriasis, but the manner in which this process contributes to the disease is not fully understood. In this study, we carried out a three-stage epigenome-wide association study to identify disease-associated differentially methylated sites using a combination of 262 skin and 48 peripheral blood mononuclear cell samples. We not only revealed genome-wide methylation patterns for psoriasis but also identified strong associations between the skin-specific DNA methylation of nine disease-associated differentially methylated sites and psoriasis (Wilcoxon ranked PBonferroni < 0.01; methylation level difference > 0.10). Further analysis revealed that these nine disease-associated differentially methylated sites were not significantly affected by genetic variations, supporting their remarkable contributions to disease status. The expression of CYP2S1, ECE1, EIF2C2, MAN1C1, and DLGAP4 was negatively correlated with DNA methylation. These findings will help us to better understand the molecular mechanism of psoriasis.

Filaggrin Gene Mutation c.3321delA Is Associated with Various Clinical Features of Atopic Dermatitis in the Chinese Han Population

Background We confirmed that the filaggrin gene mutation c.3321delA is associated with atopic dermatitis in our previous genome wide association study of the Chinese Han population. c.3321delA is the most common filaggrin gene mutation in Chinese atopic dermatitis patients but is not present in European populations. Objective To investigate the genetic model for the c.3321delA mutation and to determine the correlation between c.3321delA and atopic dermatitis clinical phenotypes in the Chinese Han population. Method The filaggrin gene mutation c.3321delA was sequenced in 1,080 atopic dermatitis patients and 908 controls from the Chinese population. The χ2 test, ANOVA,nonparametric tests and logistic regression were used to investigate the relationship between the c.3321delA genotype and atopic dermatitis clinical phenotypes in the Chinese Han population. Results Analyses of the genetic model revealed that the additive model best described the c.3321delA mutation (P = 3.09E-11, OR = 3.43, 95%CI = 2.38–4.96). Stratified analyses showed that the c.3321delA allele frequency distribution is significantly associated with concomitant skin xerosis (P = 1.68E-03, OR = 2.13,95%CI = 1.32–3.46), palmar hyperlinearity (P = 3.64E-17, OR = 4.0,95%CI = 2.86–5.70), white dermatographism (P = 4.25E-03, OR = 1.82,95%CI = 1.22–2.71), food intolerance (P = 1.51E-03, OR = 1.76,95%CI = 1.23–2.50) and disease severity ( P = 9.67E-05). Conclusion Our study indicates that the filaggrin gene mutation c.3321delA is associated with clinical phenotypes of atopic dermatitis in the Chinese Han population, which might help us gain a better understanding on the pathogenesis of atopic dermatitis.

Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo.

A Weighted Polygenic Risk Score Using 14 Known Susceptibility Variants to Estimate Risk and Age Onset of Psoriasis in Han Chinese

With numbers of common variants identified mainly through genome-wide association studies (GWASs), there is great interest in incorporating the findings into screening individuals at high risk of psoriasis. The purpose of this study is to establish genetic prediction models and evaluate its discriminatory ability in psoriasis in Han Chinese population. We built the genetic prediction models through weighted polygenic risk score (PRS) using 14 susceptibility variants in 8,819 samples. We found the risk of psoriasis among individuals in the top quartile of PRS was significantly larger than those in the lowest quartile of PRS (OR = 28.20, P < 2.0×10-16). We also observed statistically significant associations between the PRS, family history and early age onset of psoriasis. We also built a predictive model with all 14 known susceptibility variants and alcohol consumption, which achieved an area under the curve statistic of ~ 0.88. Our study suggests that 14 psoriasis known susceptibility loci have the discriminating potential, as is also associated with family history and age of onset. This is the genetic predictive model in psoriasis with the largest accuracy to date.

Exome sequencing identifies SLC17A9 pathogenic gene in two Chinese pedigrees with disseminated superficial actinic porokeratosis

Background Disseminated superficial actinic porokeratosis (DSAP) is a rare autosomal dominant genodermatosis characterised by annular lesions that has an atrophic centre and a prominent peripheral ridge distributed on sun exposed area. It exhibits high heterogeneity, and five linkage loci have been reported. The mevalonate kinase (MVK) gene located on 12q24 has been confirmed as one of the disease-causing genes. But, the pathogenesis of a large part of DSAP remains unclear so far. Methods The recruited with DSAP carried no MVK coding mutations. Exome sequencing was performed in two affected and one unaffected individual in Family 1. Cosegregation of the candidate variants was tested in other family members. Sanger sequencing in 33 individuals with familial DSAP and 19 sporadic DSAP individuals was performed for validating the causative gene. Results An average of 1.35×105 variants were generated from exome data and 133 novel NS/SS/indels were identified as being shared by two affected individuals but absent in the unaffected individual. After functional prediction, 25 possible deleterious variants were identified. In Family 1, a missense variant c.932G>A (p.Arg311Gln) in exon 10 of SLC17A9 was observed in cosegregation with the phenotype; this amino acid substitution was located in a highly conserved major facilitator superfamily (MFS) domain in multiple mammalian. One additional missense variant c.25C>T (p.Arg9Cys) in exon 2 of SLC17A9 was found in Family 2. Conclusions The result identified SLC17A9 as another pathogenic gene for DSAP, which suggests a correlation between the aberrant vesicular nucleotide transporter and the pathogenesis of DSAP.

Association of the Late Cornified Envelope-3 Genes with Psoriasis and Psoriatic Arthritis： A Systematic Review

Psoriasis (Ps) and psoriatic arthritis (PsA) are genetically complex diseases with strong genetic evidence. Recently, susceptibility genes for Ps and PsA have been identified within the late cornified envelop (LCE) gene cluster, especially the cluster 3 (LCE3) genes. It is noteworthy that the deletion of LCE3B and LCE3C (LCE3C_LCE3B-del) is significantly associated with these two diseases. Gene-gene interactions between LCE3 genes and other genes are associated with Ps and PsA. LCE3 genes also have pleiotropic effect on some autoimmune diseases, such as rheumatoid arthritis, atopic dermatitis and systemic lupus erythematosus. Further studies need to focus on the potential function of LCE3 genes in the pathogenesis of Ps and PsA in the future.

Several Critical Cell Types, Tissues, and Pathways Are Implicated in Genome-Wide Association Studies for Systemic Lupus Erythematosus

We aimed to elucidate the cell types, tissues, and pathways influenced by common variants in systemic lupus erythematosus (SLE). We applied a nonparameter enrichment statistical approach, termed SNPsea, in 181 single nucleotide polymorphisms (SNPs) that have been identified to be associated with the risk of SLE through genome-wide association studies (GWAS) in Eastern Asian and Caucasian populations, to manipulate the critical cell types, tissues, and pathways. In the two most significant cells’ findings (B lymphocytes and CD14+ monocytes), we subjected the GWAS association evidence in the Han Chinese population to an enrichment test of expression quantitative trait locus (QTL) sites and DNase I hypersensitivity, respectively. In both Eastern Asian and Caucasian populations, we observed that the expression level of SLE GWAS implicated genes was significantly elevated in xeroderma pigentosum B cells (P ≤ 1.00 × 10−6), CD14+ monocytes (P ≤ 2.74 × 10−4) and CD19+ B cells (P ≤ 2.00 × 10−6), and plasmacytoid dendritic cells (pDCs) (P ≤ 9.00 × 10−6). We revealed that the SLE GWAS-associated variants were more likely to reside in expression QTL in B lymphocytes (q1/q0 = 2.15, P = 1.23 × 10−44) and DNase I hypersensitivity sites (DHSs) in CD14+ monocytes (q1/q0 = 1.41, P = 0.08). We observed the common variants affected the risk of SLE mostly through by regulating multiple immune system processes and immune response signaling. This study sheds light on several immune cells and responses, as well as the regulatory effect of common variants in the pathogenesis of SLE.