Xianyong Yin

Genomic Dissection of Population Substructure of Han Chinese and Its Implication in Association Studies

To date, most genome-wide association studies (GWAS) and studies of fine-scale population structure have been conducted primarily on Europeans. Han Chinese, the largest ethnic group in the world, composing 20% of the entire global human population, is largely underrepresented in such studies. A well-recognized challenge is the fact that population structure can cause spurious associations in GWAS. In this study, we examined population substructures in a diverse set of over 1700 Han Chinese samples collected from 26 regions across China, each genotyped at approximately 160K single-nucleotide polymorphisms (SNPs). Our results showed that the Han Chinese population is intricately substructured, with the main observed clusters corresponding roughly to northern Han, central Han, and southern Han. However, simulated case-control studies showed that genetic differentiation among these clusters, although very small (F(ST) = 0.0002 approximately 0.0009), is sufficient to lead to an inflated rate of false-positive results even when the sample size is moderate. The top two SNPs with the greatest frequency differences between the northern Han and southern Han clusters (F(ST) > 0.06) were found in the FADS2 gene, which associates with the fatty acid composition in phospholipids, and in the HLA complex P5 gene (HCP5), which associates with HIV infection, psoriasis, and psoriatic arthritis. Ingenuity Pathway Analysis (IPA) showed that most differentiated genes among clusters are involved in cardiac arteriopathy (p < 10(-101)). These signals indicating significant differences among Han Chinese subpopulations should be carefully explained in case they are also detected in association studies, especially when sample sources are diverse.

A large-scale screen for coding variants predisposing to psoriasis.

To explore the contribution of functional coding variants to psoriasis, we analyzed nonsynonymous single-nucleotide variants (SNVs) across the genome by exome sequencing in 781 psoriasis cases and 676 controls and through follow-up validation in 1,326 candidate genes by targeted sequencing in 9,946 psoriasis cases and 9,906 controls from the Chinese population. We discovered two independent missense SNVs in IL23R and GJB2 of low frequency and five common missense SNVs in LCE3D, ERAP1, CARD14 and ZNF816A associated with psoriasis at genome-wide significance. Rare missense SNVs in FUT2 and TARBP1 were also observed with suggestive evidence of association. Single-variant and gene-based association analyses of nonsynonymous SNVs did not identify newly associated genes for psoriasis in the regions subjected to targeted resequencing. This suggests that coding variants in the 1,326 targeted genes contribute only a limited fraction of the overall genetic risk for psoriasis.

Meta-analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases.

Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.

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.

Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis

To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, Pcombined = 2.92 × 10−8, odds ratio (OR) = 1.31) and 22p11 (CABIN1 and SUSD2, rs8141797, Pcombined = 2.35 × 10−9, OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS.

Confirmation of C4 gene copy number variation and the association with systemic lupus erythematosus in Chinese Han population.

The distribution of complement component 4 (C4) gene copy number (GCN) has been validated in European populations. Meanwhile, C4 gene has been identified as a susceptibility gene for systemic lupus erythematosus (SLE). However, the association and the possible phenotype significance remain to be determined intensely in the Chinese population. This study was designed to validate the distribution of C4 GCNs in Chinese Han and the correlation between C4 GCNs and SLE using quantitative real-time polymerase chain reaction in 924 SLE patients and 1,007 controls. The results presented distribution of C4 GCNs in healthy populations and also showed that lower C4 GCN was a risk factor for SLE and higher C4 GCN was a protective factor against the disease susceptibility, which was similar to the report in the Caucasian population. Furthermore, we found the association between C4A GCN and disease subphenotypes of arthritis with SLE. We conclude that the association of C4 GCN with SLE was replicated in Chinese Han population, which highlighted the importance of C4 in SLE pathogenesis of diverse populations.

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.