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Genome-wide association analysis of Vogt-Koyanagi-Harada syndrome identifies two new susceptibility loci at 1p31.2 and 10q21.3

Nature Genetics volume 46, pages 1007–1011 (2014)Cite this article

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Abstract

To identify new genetic risk factors for Vogt-Koyanagi-Harada (VKH) syndrome, we conducted a genome-wide association study of 2,208,258 SNPs in 774 cases and 2,009 controls with follow-up in a collection of 415 cases and 2,006 controls and a further collection of 349 cases and 1,588 controls from a Han Chinese population. We identified three loci associated with VKH syndrome susceptibility (IL23R-C1orf141, rs117633859, Pcombined = 3.42 × 10−21, odds ratio (OR) = 1.82; ADO-ZNF365-EGR2, rs442309, Pcombined = 2.97 × 10−11, OR = 1.37; and HLA-DRB1/DQA1, rs3021304, Pcombined = 1.26 × 10−118, OR = 2.97). The five non-HLA genes were all expressed in human iris tissue. IL23R was also expressed in the ciliary body, and EGR2 was expressed in the ciliary body and choroid. The risk G allele of rs117633859 in the promoter region of IL23R exhibited low transcriptional activation in a cell-based reporter assay and was associated with diminished IL23R mRNA expression in human peripheral blood mononuclear cells.

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Figure 1: Genome-wide association results for 774 cases with VKH syndrome and 2,009 controls from the Han Chinese population.
Figure 2: Regional plots of association results for the two newly identified susceptibility loci for VKH syndrome at 1p31.2 and 10q21.3.

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Acknowledgements

This work was supported by the Natural Science Foundation Major International (Regional) Joint Research Project (81320108009) (P.Y.), the National Basic Research Program of China (973 Program) (2011CB510200) (P.Y.), the Key Project of the Natural Science Foundation (81130019) (P.Y.), the National Natural Science Foundation Project (31370893 (P.Y.), 81270990 (S.H.) and 81025006 (Z. Yang)), the Research Fund for the Doctoral Program of Higher Education of China (20115503110002) (P.Y.), the Clinic Key Project of the Ministry of Health (201002019) (P.Y.), the Basic Research program of Chongqing (cstc2013jcyjC10001) (P.Y.), the Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003) (P.Y.), the National Key Clinical Specialties Construction Program of China (P.Y.), the Key Project of Health Bureau of Chongqing (2012-1-003) (P.Y.), the Fund for PAR-EU Scholars Program (P.Y.) and The Youth Outstanding-notch Talent Support Program of Chongqing (S.H.). We thank H. Zhou (Zhongshan Ophthalmic Center, Sun Yat-sen University), X. Liu (Department of Ophthalmology, The Second Hospital of Jilin University), Y. Wang (The Eye Hospital of Wenzhou Medical University), H. Wang (Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University), L. Xing (Ophthalmology of Department, the First Affiliated Hospital, Harbin Medical University), R. Zhang (Department of Ophthalmology, Eye and ENT Hospital of Fudan University), Y. Shi (Department of Ophthalmology, Shanxi Eye Hospital) and C. Zhao (Department of Ophthalmology, Nanjing General Hospital of the Nanjing Military Region) for helping with sample collection, and we also thank the individuals, their families and friends who participated in this project. Some samples of cases and controls were collected in the Zhongshan Ophthalmic Center, Sun Yat-sen University. We thank Genergy Bio-technology Corporation (Shanghai) and CapitalBio Corporation (Beijing) for helping with the microarray experiment, and we also thank Beijing Genomics Institute for luciferase reporter analysis.

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  1. Zhenglin Yang and Peizeng Yang: These authors jointly directed this work.

Authors and Affiliations

  1. The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Shengping Hou, Liping Du, Bo Lei, Qi Zhang, Ke Hu, Qingyun Zhou, Jian Qi, Chaokui Wang, Yuan Tian, Zi Ye, Liang Liang, Hongsong Yu, Hong Li, Yan Zhou, Qingfeng Cao, Yunjia Liu, Lin Bai, Dan Liao & Peizeng Yang

  2. Chongqing Key Laboratory of Ophthalmology, Chongqing, China

    Shengping Hou, Liping Du, Bo Lei, Qi Zhang, Ke Hu, Qingyun Zhou, Jian Qi, Chaokui Wang, Yuan Tian, Zi Ye, Liang Liang, Hongsong Yu, Hong Li, Yan Zhou, Qingfeng Cao, Yunjia Liu, Lin Bai, Dan Liao & Peizeng Yang

  3. Chongqing Eye Institute, Chongqing, China

    Shengping Hou, Liping Du, Bo Lei, Qi Zhang, Ke Hu, Qingyun Zhou, Jian Qi, Chaokui Wang, Yuan Tian, Zi Ye, Liang Liang, Hongsong Yu, Hong Li, Yan Zhou, Qingfeng Cao, Yunjia Liu, Lin Bai, Dan Liao & Peizeng Yang

  4. Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China

    Chi Pui Pang

  5. Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

    Meifen Zhang

  6. Department of Ophthalmology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China

    Wenjuan Zhuang

  7. Department of Ophthalmology, Xingtai Eye Hospital, Xingtai, China

    Minglian Zhang

  8. The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China

    Lulin Huang, Bo Gong & Zhenglin Yang

  9. Department of Occupational Medicine and Environmental Health, School of Public Health, Nanjing Medical University, Nanjing, China

    Meilin Wang

  10. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA

    Meilin Wang & Jianfeng Xu

  11. University Clinic for Ophthalmology Maastricht, Maastricht, the Netherlands

    Yuan Tian & Aize Kijlstra

  12. School of Public Health, Fudan University, Shanghai, China

    Jianfeng Xu

  13. School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

    Zhenglin Yang

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  1. Shengping Hou
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  2. Liping Du
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Contributions

P.Y., Z. Yang and S.H. conceived and designed the study. S.H., M.W. and J.X. analyzed the GWAS data. P.Y., Z. Yang, L.D., C.P.P., Meifen Zhang, W.Z., Minglian Zhang, Q. Zhang, K.H., Q. Zhou and H.L. recruited subjects and participated in the diagnostic evaluations. S.H., L.D., L.H., K.H., J.Q., C.W., Y.T., Z. Ye, Y.Z., Y.L., L.B. and D.L. contributed to the genotyping. L.L., H.Y. and Q.C. contributed to the reagents, materials and analysis tools. S.H., B.L., B.G. and D.L. contributed to the RT-PCR or real-time PCR. S.H. and P.Y. drafted the manuscript. B.L., C.P.P., J.X., A.K. and Z. Yang helped revise the manuscript. P.Y., Z. Yang and S.H. obtained funding for this study. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Zhenglin Yang or Peizeng Yang.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Flow chart describing the present GWAS and replication studies.

Supplementary Figure 2 The principal component analysis (PCA) of GWAS samples and HapMap 270 individuals (JPT+CHB, CEU and YRI).

Distribution of the subjects used in GWAS and four HapMap polulations.

Supplementary Figure 3 Plots of the first two components derived from a principle component analysis for cases with VKH syndrome and controls used in GWAS implemented in the software package EIGENSTRAT.

Supplementary Figure 4 Genome-wide association results for non-HLA SNPs.

(a) Q-Q plots of the observed P values (y axis) versus the expected P-values (x axis) from genome-wide association results for non-HLA SNPs. (b) Manhattan plot of P values on the –log10 scale for 2,199,482 non-HLA SNPs (removed SNPs at chr 6: 28-34M) in the GWAS stage (774 VKH cases and 2,009 normal controls). The red line represents P = 1.0 × 10−8, and the blue dashed line represents P = 1.0 × 10−6.

Supplementary Figure 5 Regional plot of association results for the HLA region.

Results (-log10 P) are shown for SNPs in the 6p21.3 region flanking 400 kb on either side of the index SNPs (purple diamond). The association results for both genotyped and imputed SNPs are shown with the recombination rates estimated from the 1000 Genomes Project CHB and JPT data. The index SNP is shown in diamonds, and the r2 values of the remaining SNPs are indicated by color. The genes within the region are annotated and indicated by arrows.

Supplementary Figure 6 LD block at the IL23R-C1orf141 locus flanking SNP rs117633859 in the Han Chinese population.

Haplotype LD block was estimated for the SNPs at the IL23R-C1orf141 locus using the 1000 Genomes Project CHB data by Haploview software. The r2 values are shown in blocks. D’ ≥ 0.80, red; 0.5 ≤ D’ < 0.8, pink; 0.2 ≤ D’ < 0.5, blue; D’ < 0.2, white.

Supplementary Figure 7 The expression of IL23R in human uveal tissues and the association of SNP rs117633859 near IL23R with mRNA expression levels in normal control peripheral blood mononuclear cells (PBMCs) and luciferase activity analysis.

(a,b) The mRNA expression of IL23R in the human uveal tissues including the iris, ciliary body and choroid from four controls (lanes 1-4) using RT-PCR. (c) The mRNA expression of IL23R according to rs117633859 genotypes in human PBMCs from normal controls. A Mann-Whitney nonparametric test was used to test for significance among different genotypes of rs117633859. P < 0.05 was considered significant. Error bar: s.d. (d) The ~5 kb sequences of IL23R carrying the risk G allele or the A allele of SNP rs117633859 were cloned into a pGL3-basic vector. Luciferase activity was determined using a Modulus system (Turner Biosystems). The experiment was repeated twelve times (n = 12). An independent-samples T test was used to test for the significance of luciferase activity between risk and protective alleles of rs117633859. Error bar: s.d.

Supplementary Figure 8 The expression of C1orf141, ADO, ZNF365, EGR2 and IL23R in the human uveal tissues.

(a–e) The mRNA expression of C1orf141 (a), ADO (b), ZNF365 (c), EGR2 (d) and β-actin (e) in uveal tissues (iris, ciliary body and choroid) from four controls (lanes 1-4). (f) The mRNA expression of IL23R in the iris between VKH patients without active inflammation and controls. The iris tissue was obtained from fourteen eye donors without ocular inflammatory disease or a history of eye disease and seven VKH patients without active inflammation (obtained during iridectomy surgery to prevent secondary glaucoma). The experiment was repeated triple times (n = 3). An independent-samples T test was used to test for the significance of IL23R between VKH patients and controls.

Supplementary Figure 9 A locus-zoom plot of the IL23R expression quantitative trait locus (eQTL) effect around SNP rs117633859.

(a) The locus-zoom plot of the IL23R eQTL effect using HapMap Han Chinese in Beijing, China (CHB) from GEO data sets (GSE6536). (b) The locus-zoom plot of the IL23R eQTL effect using HapMap Han Chinese in Beijing, China (CHB) from HAPMAP3_EXPRESSION database (E-MTAB-264). Twenty SNPs including rs77258390, rs3762318, rs12563505, rs34017352, rs114661385, rs117301158, rs115009271, rs76091599, rs78865162, rs78917656, rs78597810, rs12568393, rs12561798, rs76436269, rs6693659, rs78377598, rs12564219, rs12566159, rs117282985, rs117633859 (from left to right) were enrolled in the eQTLs analysis.

Supplementary Figure 10 LD block of SNPs at the IL23R locus associated with multiple autoimmune diseases.

(a) Haplotype LD block was estimated for the IL23R SNPs associated with VKH syndrome in the present study and reported by previous study (Jiang et al. Hum. Immunol. 71, 414-417, 2010) using the 1000 Genomes Project CHB data by Haploview software. The r2 values are shown in blocks. D’ ≥ 0.80, red; 0.5 ≤ D’ < 0.8, pink; 0.2 ≤ D’ < 0.5, blue; D’ < 0.2, white. (b,c) Haplotype LD block was estimated for the IL23R SNPs associated with VKH syndrome and other autoimmune disease including ankylosing spondylitis, Crohn’s disease, ulcerative colitis and psoriasis using the present GWAS controls data (b) and cases data (c) by Haploview software. The r2 values are shown in blocks. D’ ≥ 0.80, red; 0.5 ≤ D’ < 0.8, pink; 0.2 ≤ D’ < 0.5, blue; D’ < 0.2, white. SNP rs11209026 associated with a variety of autoimmune diseases such as Crohn’s disease, psoriasis and ankylosing spondylitis is monomorphic in the Han Chinese population.

Supplementary Figure 11 Association of SNP rs442309 in ADO-ZNF365-EGR2 with gene expression levels in human lymphoblastoid cell lines.

The mRNA expression of ADO, ZNF365 and EGR2 according to rs442309 genotypes using HapMap CHB and JPT (downloaded from HAPMAP3_EXPRESSION database (E-MTAB-264)).

Supplementary Figure 12 Cluster plot of 384 DNA samples for SNP rs117633859 by TaqMan assay using AB7900 Real-Time PCR system.

Green color stand for homozygote AA. Red color stands for heterozygote AG. Blue color stands for homozygote GG. Gray color stands for no call.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1-12, Supplementary Tables 1-3, 5, 6, 9-11, 14 and 15 and Supplementary Note (PDF 2903 kb)

Supplementary Table 4

Results for associated SNPs at 1p31.2 and 10q21.3 in GWAS with VKH syndrome (P < 0.0001) (XLSX 17 kb)

Supplementary Table 7

Results for three associated loci after adjusting for two array platforms (XLSX 18 kb)

Supplementary Table 8

Summary of associated SNPs in the HLA region with VKH syndrome (XLSX 28 kb)

Supplementary Table 12

Summary of association results for IL23R and ADO-EGR2-ZNF365 genes with human diseases (XLSX 26 kb)

Supplementary Table 13

Summary of association results for multiple autoimmune diseases by GWAS (XLSX 53 kb)

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Hou, S., Du, L., Lei, B. et al. Genome-wide association analysis of Vogt-Koyanagi-Harada syndrome identifies two new susceptibility loci at 1p31.2 and 10q21.3. Nat Genet 46, 1007–1011 (2014). https://doi.org/10.1038/ng.3061

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  • DOI: https://doi.org/10.1038/ng.3061

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