Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC


We conducted a genome-wide association study of generalized vitiligo in the Chinese Han population by genotyping 1,117 cases and 1,429 controls. The 34 most promising SNPs were carried forward for replication in samples from individuals of the Chinese Han (5,910 cases and 9,916 controls) and Chinese Uygur (713 cases and 824 controls) populations. We identified two independent association signals within the major histocompatibility complex (MHC) region (rs11966200, Pcombined = 1.48 × 10−48, OR = 1.90; rs9468925, Pcombined = 2.21 × 10−33, OR = 0.74). Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles and that the association at rs9468925 might represent a previously unknown HLA susceptibility allele. We also identified one previously undescribed risk locus at 6q27 (rs2236313, Pcombined = 9.72 × 10−17, OR = 1.20), which contains three genes: RNASET2, FGFR1OP and CCR6. Our study provides new insights into the genetic basis of vitiligo.

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Figure 1: Genome-wide association results from the initial GWAS.
Figure 2: Scatter plot of the evidence of association at 6q27 for vitiligo.


  1. 1

    Hann, S.K. & Nordlund, J.J. Vitiligo (Blackwell Science, Oxford, UK, 2000).

  2. 2

    Das, S.K., Majumder, P.P., Chakraborty, R., Majumdar, T.K. & Haldar, B. Studies on vitiligo. I. Epidemiological profile in Calcutta, India. Genet. Epidemiol. 2, 71–78 (1985).

    CAS  Article  Google Scholar 

  3. 3

    Birlea, S.A., Fain, P.R. & Spritz, R.A. A Romanian population isolate with high frequency of vitiligo and associated autoimmune diseases. Arch. Dermatol. 144, 310–316 (2008).

    Article  Google Scholar 

  4. 4

    Taïeb, A. & Picardo, M. Clinical practice. Vitiligo. N. Engl. J. Med. 360, 160–169 (2009).

    Article  Google Scholar 

  5. 5

    Porter, J., Beuf, A.H., Nordlund, J.J. & Lerner, A.B. Psychological reaction to chronic skin disorders: a study of patients with vitiligo. Gen. Hosp. Psychiatry 1, 73–77 (1979).

    CAS  Article  Google Scholar 

  6. 6

    Alkhateeb, A., Fain, P.R., Thody, A., Bennett, D.C. & Spritz, R.A. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 16, 208–214 (2003).

    Article  Google Scholar 

  7. 7

    Dell'anna, M.L. & Picardo, M. A review and a new hypothesis for non-immunological pathogenetic mechanisms in vitiligo. Pigment Cell Res. 19, 406–411 (2006).

    Article  Google Scholar 

  8. 8

    Spritz, R.A. The genetics of generalized vitiligo. Curr. Dir. Autoimmun. 10, 244–257 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Zhang, X.J. et al. Characteristics of genetic epidemiology and genetic models for vitiligo. J. Am. Acad. Dermatol. 51, 383–390 (2004).

    Article  Google Scholar 

  10. 10

    Nath, S.K. et al. Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus. Am. J. Hum. Genet. 69, 1401–1406 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Alkhateeb, A. et al. Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3–p32.2. Hum. Mol. Genet. 11, 661–667 (2002).

    CAS  Article  Google Scholar 

  12. 12

    Spritz, R.A., Gowan, K., Bennett, D.C. & Fain, P.R. Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis. Am. J. Hum. Genet. 74, 188–191 (2004).

    CAS  Article  Google Scholar 

  13. 13

    Chen, J.J. et al. A novel linkage to generalized vitiligo on 4q13–q21 identified in a genomewide linkage analysis of Chinese families. Am. J. Hum. Genet. 76, 1057–1065 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Jin, Y. et al. NALP1 in vitiligo-associated multiple autoimmune disease. N. Engl. J. Med. 356, 1216–1225 (2007).

    CAS  Article  Google Scholar 

  15. 15

    Ren, Y. et al. Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo. PLoS Genet. 5, e1000523 (2009).

    Article  Google Scholar 

  16. 16

    Jin, Y., Birlea, S.A., Fain, P.R. & Spritz, R.A. Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population. J. Invest. Dermatol. 127, 2558–2562 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Zamani, M. et al. Linkage and association of HLA class II genes with vitiligo in a Dutch population. Br. J. Dermatol. 145, 90–94 (2001).

    CAS  Article  Google Scholar 

  18. 18

    Arcos-Burgos, M. et al. Vitiligo: complex segregation and linkage disequilibrium analyses with respect to microsatellite loci spanning the HLA. Hum. Genet. 110, 334–342 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Jin, Y. et al. Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N. Engl. J. Med. 362, 1686–1697 (2010).

    CAS  Article  Google Scholar 

  20. 20

    Liu, J.B. et al. Association of vitiligo with HLA-A2: a meta-analysis. J. Eur. Acad. Dermatol. Venereol. 21, 205–213 (2007).

    Article  Google Scholar 

  21. 21

    Zhang, X.J. et al. Association of HLA class I alleles with vitiligo in Chinese Hans. J. Dermatol. Sci. 35, 165–168 (2004).

    Article  Google Scholar 

  22. 22

    Taştan, H.B., Akar, A., Orkunoglu, F.E., Arca, E. & Inal, A. Association of HLA class I antigens and HLA class II alleles with vitiligo in a Turkish population. Pigment Cell Res. 17, 181–184 (2004).

    Article  Google Scholar 

  23. 23

    Han, J.W. et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234–1237 (2009).

    CAS  Article  Google Scholar 

  24. 24

    Zhang, X.J. et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat. Genet. 41, 205–210 (2009).

    CAS  Article  Google Scholar 

  25. 25

    Zhang, F.R. et al. Genomewide association study of leprosy. N. Engl. J. Med. 361, 2609–2618 (2009).

    CAS  Article  Google Scholar 

  26. 26

    Campomenosi, P. et al. Characterization of RNASET2, the first human member of the Rh/T2/S family of glycoproteins. Arch. Biochem. Biophys. 449, 17–26 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Acquati, F. et al. Cloning and characterization of a senescence inducing and class II tumor suppressor gene in ovarian carcinoma at chromosome region 6q27. Oncogene 20, 980–988 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Monti, L. et al. RNASET2 as a tumor antagonizing gene in a melanoma cancer model. Oncol. Res. 17, 69–74 (2008).

    Article  Google Scholar 

  29. 29

    Thompson, D.M. & Parker, R. The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae. J. Cell Biol. 185, 43–50 (2009).

    CAS  Article  Google Scholar 

  30. 30

    Schallreuter, K.U. et al. In vivo and in vitro evidence for hydrogen peroxide (H2O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. J. Investig. Dermatol. Symp. Proc. 4, 91–96 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Mikolajka, A. et al. Structure of the N-terminal domain of the FOP (FGFR1OP) protein and implications for its dimerization and centrosomal localization. J. Mol. Biol. 359, 863–875 (2006).

    CAS  Article  Google Scholar 

  32. 32

    Popovici, C. et al. The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1. Blood 93, 1381–1389 (1999).

    CAS  PubMed  Google Scholar 

  33. 33

    Acquaviva, C. et al. The centrosomal FOP protein is required for cell cycle progression and survival. Cell Cycle 8, 1217–1227 (2009).

    CAS  Article  Google Scholar 

  34. 34

    Schutyser, E., Struyf, S. & Van Damme, J. The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev. 14, 409–426 (2003).

    CAS  Article  Google Scholar 

  35. 35

    Le Borgne, M. et al. Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo. Immunity 24, 191–201 (2006).

    CAS  Article  Google Scholar 

  36. 36

    Birlea, S.A., Gowan, K., Fain, P.R. & Spritz, R.A. Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8. J. Invest. Dermatol. 130, 798–803 (2010).

    CAS  Article  Google Scholar 

  37. 37

    Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

    CAS  Article  Google Scholar 

  38. 38

    Levy, C. et al. Identifying a common molecular mechanism for inhibition of MITF and STAT3 by PIAS3. Blood 107, 2839–2845 (2006).

    CAS  Article  Google Scholar 

  39. 39

    Garraway, L.A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005).

    CAS  Article  Google Scholar 

  40. 40

    Imielinski, M. et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat. Genet. 41, 1335–1340 (2009).

    CAS  Article  Google Scholar 

  41. 41

    Zhang, Z. et al. The analysis of genetics and associated autoimmune diseases in Chinese vitiligo patients. Arch. Dermatol. Res. 301, 167–173 (2009).

    CAS  Article  Google Scholar 

  42. 42

    Taïeb, A. & Picardo, M. The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force. Pigment Cell Res. 20, 27–35 (2007).

    Article  Google Scholar 

  43. 43

    Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    CAS  Article  Google Scholar 

  44. 44

    Mantel, N. & Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).

    CAS  PubMed  Google Scholar 

  45. 45

    Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    CAS  Article  Google Scholar 

  46. 46

    de Bakker, P.I. et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat. Genet. 38, 1166–1172 (2006).

    CAS  Article  Google Scholar 

  47. 47

    Browning, S.R. & Browning, B.L. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am. J. Hum. Genet. 81, 1084–1097 (2007).

    CAS  Article  Google Scholar 

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We thank all study participants. We also thank J.-J. Liu, J.-M. Chen and K. Seng Sim at the Genome Institute of Singapore for performing the imputation, association and LD analyses of HLA alleles. This study was supported in part by the Key Project of the Chinese National Natural Science Foundation (No. 30530670), the Cooperation Project of the Chinese Key National Natural Science Foundation for Overseas Youth (No. 30628021) and the Anhui Provincial Special Scientific Program (2007-7).

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X.-J.Z. conceived this study and obtained financial support; X.-J.Z., Y.Z. and S.Y. designed the study; C.Q., Y.-Q.R., L.-H.X. and L.-D.S. participated in the design and were responsible for sample selection, genotyping and project management; S.-M.Z., D.-Y.H., Yang Li, X.-F.T., S.-X.X., Y.-M.L., Q.X., J.-P.G., W.-L.H., C.N., T.-M.P., Yun Li, Y.-S.L. and Z.-Y.Y. conducted sample selection and managed data; A.-E.X., X.-H.G., H.-D.C., X.-M.P., R.-N.W., C.-Z.L., J.-B.L., T.-W.G., J.-Z.Z., X.-L.W., J.W., R.-Y.Y., L.L., J.-B.Y., Y.-W.L., X.-D.W., W.-S.H., Y.Y., Y.Z., W.-S.W., P.-L.D., K.L., X.-J.K., Y.-Q.L., L.S., Z.-F.L. and S.-Q.X. undertook recruitment, collected phenotype data, undertook related data handling and calculation and obtained biological samples; H.-Q.J., M.S., C.-Y.Z., Y.W., G.C., P.L., J.Z., H.C., M.L., X.Z., H.-Y.T., S.-M.H., S.Y. and C.-F.H. performed genotyping analyses; X.-B.Z., S.-Q.Z., X.-D.Z., X.-Y.Y. and F.-Y.Z. undertook data processing, statistical analysis and bioinformatics investigations; all the authors contributed to the final paper.

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Correspondence to Youwen Zhou or Xue-Jun Zhang.

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Quan, C., Ren, Y., Xiang, L. et al. Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nat Genet 42, 614–618 (2010).

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