Vitiligo pp 237-251 | Cite as


  • Richard A. SpritzEmail author


Large-scale epidemiological surveys have shown that most cases of vitiligo occur sporadically, though about 15–20% of patients report one or more affected relatives. The rationale for genetic studies of vitiligo susceptibility is that underlying genes are involved in mediating disease causation, either increasing or decreasing risk (protective). Three different general approaches have been used to identify genes that mediate vitiligo susceptibility: the candidate gene approach, the genome-wide approach, and the gene expression approach. Extensive experience has proven that the only analytic approach that produces verified discovery of bona fide disease genes is the genome-wide approach. Retrospective analyses of candidate gene studies have shown that the vast majority of claimed candidate gene associations represent false-positives. Accordingly, the candidate gene approach is no longer considered valid for de novo disease gene discovery and is reserved for confirmatory studies only. Similarly, almost all genes that exhibit major expression differences between disease and non-disease states turn out to not correspond to causal genes, but instead represent secondary effects, and thus likewise gene expression studies have generally not led to the discovery of genes that are causal for complex diseases. Indeed, none of the genes initially suggested on the basis of the expression approach now appear to be involved in vitiligo causation at all. In contrast, genome-wide genetic analyses, particularly genome-wide association studies (GWAS), have proven a remarkably robust approach to disease gene discovery, yielding findings that are highly reproducible and which, in aggregate, have provided dramatic advances in understanding the biological basis of many different complex diseases, including vitiligo. Reported candidate gene associations and expression difference findings that are not observed in well-powered GWAS of the same population are not now considered to be valid indications of disease-causal genes and thus will not be discussed here.



This work was supported by grants AR056292 and AR065951 from the National Institutes of Health.


  1. 1.
    Alkhateeb A, Fain PR, Thody A, et al. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their relatives. Pigment Cell Res. 2003;16:208–14.PubMedGoogle Scholar
  2. 2.
    Alkhateeb A, Stetler GL, Old W, et al. Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-p32.2. Hum Mol Genet. 2002;11:661–7.PubMedGoogle Scholar
  3. 3.
    Birlea SA, Fain PR, Spritz RA. A Romanian population isolate with high frequency of vitiligo and associated autoimmune diseases. Arch Dermatol. 2008;144:310–6.PubMedGoogle Scholar
  4. 4.
    Hafez M, Sharaf L, El-Nabi SMA. The genetics of vitiligo. Acta Dermatovener (Stockh). 1983;63:249–51.Google Scholar
  5. 5.
    Das SK, Majumder PP, Chakraborty R, et al. Studies on vitiligo. I. Epidemiological profile in Calcutta, India. Genet Epidemiol. 1985;2:71–8.PubMedGoogle Scholar
  6. 6.
    Das SK, Majumder PP, Majumdar TK, et al. Studies on vitiligo. II. Familial aggregation and genetics. Genet Epidemiol. 1985;2:255–62.PubMedGoogle Scholar
  7. 7.
    Bhatia PS, Mohan L, Pandey ON, et al. Genetic nature of vitiligo. J Dermatol Sci. 1992;4:180–4.PubMedGoogle Scholar
  8. 8.
    Carnevale A, Zavala C, Castillo VD, et al. Analisis genetico de 127 families con vitiligo. Rev Invest Clin. 1980;32:37–41.PubMedGoogle Scholar
  9. 9.
    Majumder PP, Das SK, Li CC. A genetical model for vitiligo. Am J Hum Genet. 1988;43:119–25.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol. 1993;129:994–8.PubMedGoogle Scholar
  11. 11.
    Mehta NR, Shah KC, Theodore C, et al. Epidemiological study of vitiligo in Surat area, South Gujarat. Indian J Med Res. 1973;61:145–54.PubMedGoogle Scholar
  12. 12.
    Nath SK, Majumder PP, Nordlund JJ. Genetic epidemiology of vitiligo: multilocus recessivity cross-validated. Am J Hum Genet. 1994;55:981–90.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Sun X, Xu A, Wei X, et al. Genetic epidemiology of vitiligo: a study of 815 probands and their families from south China. Int J Dermatol. 2006;45:1176–81.PubMedGoogle Scholar
  14. 14.
    Laberge G, Mailloux CM, Gowan K, et al. Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res. 2005;18:300–5.PubMedGoogle Scholar
  15. 15.
    Howitz J, Brodthagen H, Schwartz M, et al. Prevalence of vitiligo: epidemiological survey of the Isle of Bornholm, Denmark. Arch Dermatol. 1977;113:47–52.PubMedGoogle Scholar
  16. 16.
    Alkhateeb A, Fain PR, Spritz RA. Candidate functional promoter variant in the FOXD3 melanoblast developmental regulator gene in autosomal dominant vitiligo. J Investig Dermatol. 2005;125:388–91.PubMedGoogle Scholar
  17. 17.
    Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore). 1981;60:355–62.Google Scholar
  18. 18.
    Addison T. (1855). On the constitutional and local effects of disease of the suprarenal capsules. In: A collection of the published writing of the late Thomas Addison, M.D., physician to Guy’s Hospital. New Sydenham Society, London 1868. 1855. Med Classics. 1937;2:244–93.. Reprinted.Google Scholar
  19. 19.
    Cunliffe WJ, Hall R, Newell DJ, et al. Vitiligo, thyroid disease and autoimmunity. Br J Dermatol. 1968;80:135–9.PubMedGoogle Scholar
  20. 20.
    Schallreuter KU, Lemke R, Brandt O, et al. Vitiligo and other diseases: coexistence or true association? Dermatology. 1994;188:269–75.PubMedGoogle Scholar
  21. 21.
    Dawber RP. Integumentary associations of pernicious anemia. Br J Dermatol. 1970;82:221–3.PubMedGoogle Scholar
  22. 22.
    Grunnet I, Howitz J. Vitiligo and pernicious anemia. Arch Dermatol. 1979;101:82–5.Google Scholar
  23. 23.
    Zelissen PM, Bast EJ, Croughs RJ. Associated autoimmunity in Addison’s disease. J Autoimmun. 1995;8:121–30.PubMedGoogle Scholar
  24. 24.
    Sharma VK, Dawn G, Kumar B. Profile of alopecia areata in Northern India. Int J Dermatol. 1996;35:22–7.PubMedGoogle Scholar
  25. 25.
    Sharma VK, Kumar V, Dawn G. A clinical study of childhood alopecia areata in Chandigarh, India. Pediatr Dermatol. 1996;13:372–7.PubMedGoogle Scholar
  26. 26.
    Handa S, Kaur I. Vitiligo: clinical findings in 1436 patients. J Dermatol. 1999;26:653–7.PubMedGoogle Scholar
  27. 27.
    Handa S, Dogra S. Epidemiology of childhood vitiligo: a study of 625 patients from north India. Pediatr Dermatol. 2003;20:207–10.PubMedGoogle Scholar
  28. 28.
    Onunu AN, Kubeyinje EP. Vitiligo in the Nigerian African: a study of 351 patients in Benin City, Nigeria. Int J Dermatol. 2003;42:800–2.PubMedGoogle Scholar
  29. 29.
    Hirschhorn JN, Lohmueller K, Byrne E. A comprehensive review of genetic association studies. Genet Med. 2002;4:45–61.PubMedGoogle Scholar
  30. 30.
    Ioannidis JPA, Tarone R, McLaughlin JK. The false-positive to false-negative ratio in epidemiologic studies. Epidemiology. 2011;22:450–6.PubMedGoogle Scholar
  31. 31.
    Shen C, Gao J, Sheng Y, et al. Genetic susceptibility to vitiligo GWAS approaches for identifying vitiligo susceptibility genes and loci. Front Genet. 2016;7:3.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Spritz RA, Andersen G. Genetics of vitiligo. Dermatol Clin. 2017;35:245.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Ando I, Chi HI, Nakagawa H, et al. Difference in clinical features and HLA antigens between familial and non-familial vitiligo of non-segmental type. Br J Dermatol. 1993;129:408–10.PubMedGoogle Scholar
  34. 34.
    Arcos-Burgos M, Parodi E, Salgar M, et al. Vitiligo: complex segregation and linkage disequilibrium analyses with respect to microsatellite loci spanning the HLA. Hum Genet. 2002;110:334–42.PubMedGoogle Scholar
  35. 35.
    Finco O, Cuccia M, Martinetti M, et al. Age of onset in vitiligo: relationship with HLA supratypes. Clin Genet. 1991;39:48–54.PubMedGoogle Scholar
  36. 36.
    Foley LM, Lowe NJ, Misheloff E, et al. Association of HLA-DR4 with vitiligo. J Am Acad Dermatol. 1983;8:39–40.PubMedGoogle Scholar
  37. 37.
    Liu JB, Li M, Chen H, et al. Association of vitiligo with HLA-A2: a meta-analysis. J Eur Acad Dermatol Venereol. 2007;21:205–13.PubMedGoogle Scholar
  38. 38.
    Schallreuter KU, Levenig C, Kühnl P, et al. Histocompatibility antigens in vitiligo: Hamburg study on 102 patients from northern Germany. Dermatology. 1993;187:186–92.PubMedGoogle Scholar
  39. 39.
    Tastan HB, Akar A, Orkunoglu FE, et al. Association of HLA class I antigens and HLA class II alleles with vitiligo in a Turkish population. Pigment Cell Res. 2004;17:181–4.PubMedGoogle Scholar
  40. 40.
    Xia Q, Zhou WM, Liang YH, et al. MHC haplotypic association in Chinese Han patients with vitiligo. J Eur Acad Dermatol Venereol. 2006;20:941–6.PubMedGoogle Scholar
  41. 41.
    Zamani M, Spaepen M, Sghar SS, et al. Linkage and association of HLA class II genes with vitiligo in a Dutch population. Br J Dermatol. 2001;145:90–4.PubMedGoogle Scholar
  42. 42.
    Kemp EH, Ajjan RA, Waterman EA, et al. Analysis of a microsatellite polymorphism of the cytotoxic T-lymphocyte antigen-4 gene in patients with vitiligo. Br J Dermatol. 1999;140:73–8.PubMedGoogle Scholar
  43. 43.
    Birlea SA, LaBerge GS, Procopciuc LM, et al. CTLA4 and generalized vitiligo: two genetic association studies and a meta-analysis of published data. Pigment Cell Melanoma Res. 2009;22:230–4.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Blomhoff A, Kemp EH, Gawkrodger DJ, et al. CTLA4 polymorphisms are associated with vitiligo, in patients with concomitant autoimmune diseases. Pigment Cell Res. 2005;18:55–8.PubMedGoogle Scholar
  45. 45.
    Jin Y, Andersen G, Yorgov D, et al. Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat Genet. 2016;48:1418–24.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Cantón I, Akhtar S, Gavalas NG, et al. A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo. Genes Immun. 2005;6:584–7.PubMedGoogle Scholar
  47. 47.
    Laberge G, Birlea SA, Fain PR, et al. The PTPN22 -1858C>T (R620W) functional polymorphism is associated with generalized vitiligo in the Romanian population. Pigment Cell Melanoma Res. 2008;21:206–8.PubMedGoogle Scholar
  48. 48.
    Laberge G, Fain PR, Bennett DC, et al. Family-based association analysis of generalized vitiligo confirms association with PTPN22 but not CTLA4. J Investig Dermatol. 2008;128:1757. Scholar
  49. 49.
    Nath SK, Kelly JA, Namjou B, et al. Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus. Am J Hum Genet. 2001;69:1401–6.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Spritz RA. The genetics of generalized vitiligo autoimmune pathways and an inverse relationship with malignant melanoma. Genome Med. 2010;2:78.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Jin Y, Birlea SA, Fain PR, et al. Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population. J Investig Dermatol. 2007;127:2558–62.PubMedGoogle Scholar
  52. 52.
    Jin Y, Mailloux CM, Gowan K, et al. NALP1 in vitiligo-associated multiple autoimmune disease. New Engl J Med. 2007;356:1216–25.PubMedGoogle Scholar
  53. 53.
    Faustin B, Lartigue L, Bruey J-M, et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell. 2007;25:713–24.PubMedGoogle Scholar
  54. 54.
    Bruey J-M, Bruey-Sedano N, Luciano F, et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell. 2007;129:45–56.PubMedGoogle Scholar
  55. 55.
    Levandowski CB, Mailloux CM, Ferrara TM, et al. NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome. Proc Natl Acad Sci U S A. 2013;110:2952–6.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Schunter JA, Löffler D, Wiesner T, et al. A novel FoxD3 variant is associated with vitiligo and elevated thyroid autoantibodies. J Clin Endocrinol Metab. 2015;100:E1335–42.PubMedGoogle Scholar
  57. 57.
    Fain PR, Gowan K, LaBerge GS, et al. A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci. Am J Hum Genet. 2003;72:1560–4.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Spritz RA, Gowan K, Bennett DC, et al. 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. 2004;74:188–91.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Chen JJ, Huang W, Gui JP, et al. A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families. Am J Hum Genet. 2005;76:1057–65.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Liang Y, Yang S, Zhou Y, et al. Evidence for two susceptibility loci on chromosomes 22q12 and 6p21-p22 in Chinese generalized vitiligo families. J Investig Dermatol. 2007;127:2552–7.PubMedGoogle Scholar
  61. 61.
    Ren Y, Yang S, Xu S, et al. Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo. PLoS Genet. 2009;5:e1000523.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Birlea SA, Gowan K, Fain PR, et al. Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8. J Investig Dermatol. 2009;130:798–803.PubMedGoogle Scholar
  63. 63.
    Jin Y, Birlea SA, Fain PR, et al. Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. New Engl J Med. 2010;362:1686–97.PubMedGoogle Scholar
  64. 64.
    Jin Y, Birlea SA, Rain PR, et al. Common variants in FOXP1 are associated with generalized vitiligo. Nat Genet. 2010;42:576–8.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Jin Y, Birlea SA, Fain PR, et al. Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat Genet. 2012;44:676–81.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Quan C, Ren YQ, Xiang LH, et al. Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nat Genet. 2010;42:614–8.PubMedGoogle Scholar
  67. 67.
    Tang XF, Zhang Z, Hu DY, et al. Association analyses identify three susceptibility loci for vitiligo in the Chinese Han population. J Invest Dermatol. 2013;133:403–10.PubMedGoogle Scholar
  68. 68.
    Sun Y, Zuo X, Zheng X, et al. A comprehensive association analysis confirms ZMIZ1 to be a susceptibility gene for vitiligo in Chinese population. J Med Genet. 2014;51:345–53.PubMedGoogle Scholar
  69. 69.
    Jin Y, Hayashi M, Fain PR, et al. Major association of vitiligo with HLA-A*02:01 in Japanese. Pigment Cell Melanoma Res. 2015;28:360–2.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Birlea SA, Ahmad FJ, Uddin RM, et al. Association of generalized vitiligo with MHC class II loci in patients from the Indian subcontinent. J Invest Dermatol. 2013;133:1369–72.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Cheong KA, Kim NH, Noh M, et al. three new single nucleotide polymorphisms identified by a genome-wide association study in Korean patients with vitiligo. J Korean Med Sci. 2013;28:775–9.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Jin Y, Birlea SA, Fain PR, et al. Genome-wide analysis identifies a quantitative trait locus in the MHC class II region associated with generalized vitiligo age of onset. J Investig Dermatol. 2011;13:1138–312.Google Scholar
  73. 73.
    Das PK, van den Wijngaard RMJGJ, Wankowicz-Kalinska A, et al. A symbiotic concept of autoimmunity and tumour immunity: lessons from vitiligo. Trends Immunol. 2001;22:130–6.PubMedGoogle Scholar
  74. 74.
    Paradisi A, Tabolli S, Didona B, et al. Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 patients with vitiligo. J Am Acad Dermatol. 2014;71:1110–6.PubMedGoogle Scholar
  75. 75.
    Teulings HE, Oerkamp M, Ceylan E, et al. Decreased risk of melanoma in patients with vitiligo a survey among 1307 patients and their partners. Br J Dermatol. 2013;168:162–71.PubMedGoogle Scholar
  76. 76.
    Nakamura Y, Tanaka R, Teraoto Y, et al. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study. J Dermatol. 2017;44:117. Scholar
  77. 77.
    Szklarczyk D, Morris JH, Cook H, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45:D362–8.Google Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Human Medical Genetics and Genomics ProgramUniversity of Colorado School of MedicineAuroraUSA
  2. 2.Department of PediatricsUniversity of Colorado School of MedicineAuroraUSA

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