Genetics of Vitiligo


Vitiligo is an autoimmune disease that results in destruction of skin melanocytes and patches of white skin and hair. Family studies of vitiligo demonstrated that a strong, but complex genetic component underlies disease risk and that vitiligo often occurs with other autoimmune diseases, suggesting shared autoimmune susceptibility. Genome‐wide linkage and association studies have identified over 50 vitiligo susceptibility loci, with most loci harbouring genes involved in immune regulation, apoptosis or melanocyte function. The identified loci fit together in a model of melanocyte‐directed autoimmunity, and many loci are shared with other autoimmune diseases. Surprisingly, some genetic vitiligo susceptibility alleles are inversely associated with melanoma, suggesting that vitiligo represents enhanced immune surveillance against melanoma. Genetic studies of vitiligo have greatly advanced understanding of vitiligo pathobiology and may additionally provide insights into melanoma and other autoimmune disease.

Key Concepts

  • Vitiligo is a multifactorial disease, in which multiple genetic and environmental factors contribute to disease risk.
  • The genetic architecture of vitiligo is typically (and perhaps always) polygenic, with a strong genetic component underlying disease risk.
  • Over 50 genetic loci have been associated with vitiligo risk; these loci fit together in a model of melanocyte‐directed autoimmune pathobiology.
  • Most variants associated with vitiligo are in noncoding regions and presumably affect gene regulation. Nevertheless, some associated coding variants and physical interaction among proteins encoded by some vitiligo susceptibility genes provide special insights into pathogenesis.
  • Vitiligo shares many genetic risk factors with other autoimmune diseases with which it is epidemiologically associated, supporting a component of common autoimmune pathogenesis.

Keywords: vitiligo; autoimmunity; linkage analysis; genome‐wide association study; genetic studies

Figure 1. A woman with generalised vitiligo. Source: Spritz, Licensed under CC by 4.0.
Figure 2. Shared genetic associations of vitiligo with other autoimmune diseases. Black circles indicate a genetic association in the same region in vitiligo and with the other autoimmune disease. Only associations identified by GWAS and meeting the genome‐wide significance criterion (P < 5 × 10−8) are shown. RA, rheumatoid arthritis; T1D, type 1 diabetes mellitus; IBD, inflammatory bowel disease; AITD, autoimmune thyroid disease; MS, multiple sclerosis; SLE, systemic lupus erythematosus; MG, myasthenia gravis.
Figure 3. General framework of vitiligo pathogenesis. Autoreactive T‐lymphocytes escape negative selection (in this example, autoreactive T‐lymphocytes recognise melanocytic peptide antigen derived from OCA2). At the site of skin damage, DAMPs are released, activating a skin dendritic cell, which then phagocytoses debris from damaged melanocytes, resulting in presentation of peptide antigen from OCA2 on its cell surface. The autoreactive T helper lymphocyte recognises the OCA2 peptide presented on the cell surface the dendritic cell and releases cytokines that activate an OCA2‐autoreactive cytotoxic T‐lymphocyte, resulting in cytolysis of a healthy melanocyte presenting the OCA2 peptide antigen. Reproduced with permission from Spritz and Andersen . © Elsevier.


Abdel‐Malek ZA, Swope VB, Starner RJ, et al. (2014) Melanocortins and the melanocortin 1 receptor, moving translationally towards melanoma prevention. Archives of Biochemistry and Biophysics 563: 4–12.

Alikhan A, Felsten LM, Daly M and Petronic‐Rosic V (2011) Vitiligo: a comprehensive overview. Journal of the American Academy of Dermatology 65 (3): 473–491.

Alkhateeb A, Stetler GL, Old W, et al. (2002) Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3–p32.2. Human Molecular Genetics 11 (6): 661–667.

Alkhateeb A, Fain PR, Thody A, Bennett DC and Spritz RA (2003) Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Research 16 (3): 208–214.

Alkhateeb A, Fain PR and Spritz RA (2005) Candidate functional promoter variant in the FOXD3 melanoblast developmental regulator gene in autosomal dominant vitiligo. Journal of Investigative Dermatology 125 (2): 388–391.

Arcos‐Burgos M, Parodi E, Salgar M, et al. (2002) Vitiligo: complex segregation and linkage disequilibrium analyses with respect to microsatellite loci spanning the HLA. Human Genetics 110 (4): 334–342.

Ben S, Jin Y, Santorico SA and Spritz RA (2018) Genome‐wide association of PVT1 with vitiligo. Journal of Investigative Dermatology 138 (8): 1884–1886.

Birlea SA, Fain PR and Spritz RA (2008) A Romanian population isolate with high frequency of vitiligo and associated autoimmune diseases. Archives of Dermatology 144 (3): 310–316.

Birlea SA, Gowan K, Fain PR and Spritz RA (2010) Genome‐wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8. Journal of Investigative Dermatology 130 (3): 798–803.

Cavalli G, Hayashi M, Jin Y, et al. (2016) MHC class II super‐enhancer increases surface expression of HLA‐DR and HLA‐DQ and affects cytokine production in autoimmune vitiligo. Proceedings of the National Academy of Sciences of the United States of America 113 (5): 1363–1368.

Chen JJ, Huang W, Gui JP, et al. (2005) A novel linkage to generalized vitiligo on 4q13‐q21 identified in a genomewide linkage analysis of Chinese families. American Journal of Human Genetics 76 (6): 1057–1065.

Das SK, Majumder PP, Majumdar TK and Haldar B (1985) Studies on vitiligo. II. Familial aggregation and genetics. Genetic Epidemiology 2 (3): 255–262.

Das PK, van den Wijngaard RM, Wankowicz‐Kalinska A and Le Poole IC (2001) A symbiotic concept of autoimmunity and tumour immunity: lessons from vitiligo. Trends in Immunology 22 (3): 130–136.

Fain PR, Gowan K, LaBerge GS, et al. (2003) A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci. American Journal of Human Genetics 72 (6): 1560–1564.

Ferrara TM, Jin Y, Gowan K, Fain PR and Spritz RA (2013) Risk of generalized vitiligo is associated with the common 55R‐94A‐247H variant haplotype of GZMB (encoding granzyme B). Journal of Investigative Dermatology 133 (6): 1677–1679.

Hafez M, Sharaf L and Abd el‐Nabi SM (1983) The genetics of vitiligo. Acta Dermato‐Venereologica 63 (3): 249–251.

Hayashi M, Jin Y, Yorgov D, et al. (2016) Autoimmune vitiligo is associated with gain‐of‐function by a transcriptional regulator that elevates expression of HLA‐A*02:01 in vivo. Proceedings of the National Academy of Sciences of the United States of America 113 (5): 1357–1362.

Hirschhorn JN, Lohmueller K, Byrne E and Hirschhorn K (2002) A comprehensive review of genetic association studies. Genetics in Medicine 4 (2): 45–61.

Jin Y, Mailloux CM, Gowan K, et al. (2007) NALP1 in vitiligo‐associated multiple autoimmune disease. New England Journal of Medicine 356 (12): 1216–1225.

Jin Y, Birlea SA, Fain PR, et al. (2010a) Common variants in FOXP1 are associated with generalized vitiligo. Nature Genetics 42 (7): 576–578.

Jin Y, Birlea SA, Fain PR, et al. (2010b) Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. New England Journal of Medicine 362 (18): 1686–1697.

Jin Y, Ferrara T, Gowan K, et al. (2012a) Next‐generation DNA re‐sequencing identifies common variants of TYR and HLA‐A that modulate the risk of generalized vitiligo via antigen presentation. Journal of Investigative Dermatology 132 (6): 1730–1733.

Jin Y, Birlea SA, Fain PR, et al. (2012b) Genome‐wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nature Genetics 44 (6): 676–680.

Jin Y, Andersen G, Yorgov D, et al. (2016) Genome‐wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nature Genetics 48 (11): 1418–1424.

Jin Y, Andersen GH, Santorico SA and Spritz RA (2017) Multiple functional variants of IFIH1, a gene involved in triggering innate immune responses, protect against vitiligo. Journal of Investigative Dermatology 137 (2): 522–524.

Krüger C and Schallreuter KU (2012) A review of the worldwide prevalence of vitiligo in children/adolescents and adults. International Journal of Dermatology 51 (10): 1206–12.

Kumar S, Nayak CS, Padhi T, et al. (2014) Epidemiological pattern of psoriasis, vitiligo and atopic dermatitis in India: hospital‐based point prevalence. Indian Dermatology Online Journal 5 (suppl. 1): S6–8.

Latz E, Xiao TS and Stutz A (2013) Activation and regulation of the inflammasomes. Nature Reviews Immunology 13 (6): 397–411.

Levandowski CB, Mailloux CM, Ferrara TM, et al. (2013) NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin‐1beta processing via the NLRP1 inflammasome. Proceedings of the National Academy of Sciences of the United States of America 110 (8): 2952–2956.

Liang Y, Yang S, Zhou Y, et al. (2007) Evidence for two susceptibility loci on chromosomes 22q12 and 6p21‐p22 in Chinese generalized vitiligo families. Journal of Investigative Dermatology 127 (11): 2552–2557.

Looney BM, Xia CQ, Concannon P, Ostrov DA and Clare‐Salzler MJ (2015) Effects of type 1 diabetes‐associated IFIH1 polymorphisms on MDA5 function and expression. Current Diabetes Reports 15 (11): 96.

Majumder PP, Das SK and Li CC (1988) A genetical model for vitiligo. American Journal of Human Genetics 43 (2): 119–125.

Nath SK, Majumder PP and Nordlund JJ (1994) Genetic epidemiology of vitiligo: multilocus recessivity cross‐validated. American Journal of Human Genetics 55 (5): 981–990.

Nath SK, Kelly JA, Namjou B, et al. (2001) Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo‐related systemic lupus erythematosus. American Journal of Human Genetics 69 (6): 1401–1406.

Paradisi A, Tabolli S, Didona B, et al. (2014) Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 patients with vitiligo. Journal of the American Academy of Dermatology 71 (6): 1110–1116.

Picardo M and Taïeb A (eds) (2018) Vitiligo. Heidelberg and New York: Springer.

Quan C, Ren YQ, Xiang LH, et al. (2010) Genome‐wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nature Genetics 42 (7): 614–618.

Ren Y, Yang S, Xu S, et al. (2009) Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo. PLoS Genetics 5 (6): e1000523.

Schunter JA, Löffler D, Wiesner T, et al. (2015) A novel FoxD3 variant is associated with vitiligo and elevated thyroid auto‐antibodies. Journal of Clinical Endocrinology and Metabolism 100 (10): E1335–E1342.

Spritz RA, Gowan K, Bennett DC and Fain PR (2004) Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis. American Journal of Human Genetics 74 (1): 188–191.

Spritz RA (2010) The genetics of generalized vitiligo: autoimmune pathways and an inverse relationship with malignant melanoma. Genome Medicine 2 (10): 78.

Spritz RA and Andersen GH (2017) Genetics of vitiligo. Dermatologia Clinica 35 (2): 245–255.

Sun Y, Zuo X, Zheng X, et al. (2014) A comprehensive association analysis confirms ZMIZ1 to be a susceptibility gene for vitiligo in Chinese population. Journal of Medical Genetics 51 (5): 345–353.

Tang XF, Zhang Z, Hu DY, et al. (2013) Association analyses identify three susceptibility Loci for vitiligo in the Chinese Han population. Journal of Investigative Dermatology 133 (2): 403–410.

Teulings HE, Overkamp M, Ceylan E, et al. (2013) Decreased risk of melanoma and nonmelanoma skin cancer in patients with vitiligo: a survey among 1307 patients and their partners. British Journal of Dermatology 168 (1): 162–171.

Teulings HE, Limpens J, Jansen SN, et al. (2015) Vitiligo‐like depigmentation in patients with stage III–IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta‐analysis. Journal of Clinical Oncology 33 (7): 773–781.

Theofilopoulos AN, Kono DH and Baccala R (2017) The multiple pathways to autoimmunity. Nature Immunology 18 (7): 716–724.

Xu S, Zhou Y, Yang S, et al. (2010) Platelet‐derived growth factor receptor alpha gene mutations in vitiligo vulgaris. Acta Dermato‐Venereologica 90 (2): 131–135.

Yang C, Wu J, Zhang X, et al. (2018) Fine‐mapping analysis of the MHC region for vitiligo based on a new Han‐MHC reference panel. Gene 648: 76–81.

Zhang XJ, Liu JB, Gui JP, et al. (2004) Characteristics of genetic epidemiology and genetic models for vitiligo. Journal of the American Academy of Dermatology 51 (3): 383–390.

Further Reading

Birlea SA, Spritz RA and Norris DA (2012) Vitiligo. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ and Wolff K (eds) Fitzpatrick's Dermatology in General Medicine, 8th edn, pp. 792–803. New York: McGraw‐Hill.

Bolognia JL, Norlund JJ, Ortonne J and Le Poole C (2006) Genetic hypomelanoses: acquired depigmentation. In: Boissy RE, Hearing VJ, King RA, Oetting WS and Ortonne J (eds) The Pigmentary System: Physiology and Pathophysiology, 2nd edn, pp. 551–598. Malden: Blackwell Publishing.

Richmond JM, Frisoli ML and Harris JE (2013) Innate immune mechanisms in vitiligo: danger from within. Current Opinion in Immunology 25: 676–682.

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Roberts, Genevieve HL, and Spritz, Richard A(Dec 2018) Genetics of Vitiligo. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026934]