The first vitiligo genetic linkage study performed on the major histocompatibility complex (MHC) reported the linkage of various genetic markers located on human leukocyte antigen (HLA) gene locus [18–20]. However, the linkage analysis in families with vitiligo-related systemic lupus erythematosus identified SLEV1 locus [21] and subsequently reported NLRP1 [22] located on chromosome 17, as one of the novel vitiligo susceptibility loci. The genome-wide linkage studies also revealed the various other susceptibility loci in different ethnic populations, e.g., chromosome 1, 7, 8, 9, 11, 13, 19, and 21 (Caucasians) [23, 24] and chromosome 4, 6, and 22 (Chinese) [20, 23–25]; some of these loci are also confirmed by GWAS.

This approach has been first successfully used to identify the single nucleotide polymorphism (SNP) for CTLA-4 gene locus [26] in vitiligo; however, CTLA-4 locus has been associated with various other autoimmune diseases [27]. Recently, Birlea et al. [28] reported a comprehensive list of 33 vitiligo candidate genes (Table 19.1), but only three genes (TSLP, XBP1, FOXP3) were supported by GWAS studies [29].

The first vitiligo GWAS was carried out in a specific population of Northwestern Romania with a high prevalence of vitiligo and other autoimmune diseases, and it found an association of vitiligo with SMOC2 gene located at distal chromosome 6q27 (in the vicinity of IDDM8, a linkage and association signal for type I diabetes mellitus and rheumatoid arthritis). Among the Caucasian and Chinese populations with vitiligo, this gene was also detected in the GWAS done [29–32]. To date, these particular populations carry three large GWAS of vitiligo, while a small gene-centric GWAS of vitiligo was reported in Indian–Pakistani patients [32–36]. These studies collectively identified 30 vitiligo susceptibility loci in Caucasians (Table 19.1). The subsequent parallel studies in the Chinese population have detected nine vitiligo susceptibility loci, suggesting some common susceptibility genes (LPP, the HLA class I gene region, CCR6, IL2RA, IKZF4, and C1QTNF6) between Caucasian and Chinese [37]. There is no major GWAS study performed in the Indian population, which is required for understanding the genetic aspect of vitiligo in this population.

The first sequencing study was performed for GTP-cyclohydrolase I gene (GCH1) that reported the association of vitiligo with GCH1 mutations. However, the findings were proven false much later [38, 39]. Over the years, DNA sequencing was performed for many candidate genes (ASIP, MC1R, MYG1/c12orf10, and POMC), but none showed significant differences [40–43].

Recently, the more robust next-generation DNA re-sequencing is being used to identify sequence variation. Sequencing of both HLA-A and TYR in Caucasian vitiligo patients had shown that the predominant HLA-A vitiligo-associated susceptibility allele is HLA-A*02:01:01:01, and the two common non-synonymous substitutions of TYR, S192Y and R402Q, exert both individual and synergistic protective effects [44].

The first gene expression study identified a gene VIT1 (FBXO11), which was downregulated in vitiligo melanocytes, but its role in vitiligo development remains uncertain [45]. In the recent years, many genome-wide expression studies have been performed reporting many differentially expressed genes in vitiligo patients, but none can be proven to be the causal factor of vitiligo.

To date, there are approximately 36 (confirmed and suggestive) susceptibility loci identified for generalized vitiligo among various ethnic populations. Immunoregulatory proteins are approximately encoded by 90 %, while the 10 % encode melanocyte proteins, suggesting the major involvement of immune parameters and hence strengthening the autoimmune theory of pathogenesis.

The autoimmune hypothesis is the most popular theory for the non-segmental and generalized type of vitiligo. Stronger evidence for this theory comes from the higher frequency of concomitant autoimmune diseases in vitiligo patients and response of vitiligo to treatment with immunosuppressives [46, 47].

Inflammatory cell infiltrates were noticed at the margin of vitiligo macules [48]. The epidermis-infiltrating T cells revealed an amplification of the CD8/CD4 ratio and IL-2 receptor expression suggesting that melanocyte obliteration could be cytotoxic CD8+ T cell mediated [49].

Many studies have shown the potential role of cytokines in the causation of vitiligo. Vitiligo skin showed significantly increased expression of IL-10, interferon-γ (IFN-γ), and tumor necrosis factor α (TNF-α) when compared to control skin. Levels of Th2 cytokine IL-10 were also found to be increased in lesional skin [50]. This explains the mechanism of action of tacrolimus in vitiligo, which potentially suppresses the Th1 response via the Th2 cytokine IL-10 suppression. Recently, elevated IL-17 levels have been found in both the lesional skin and sera of the vitiligo patients compared to controls, and it showed a positive correlation with the disease duration [51].

Humoral immunity has also been proposed to contribute to the autoimmune hypothesis of vitiligo pathogenesis. In a study by Kemp et al., 23 % of the non-segmental vitiligo patients were positive for tyrosine hydroxylase antibodies, an enzyme essential for melanogenesis pathway [52]. Harning et al., on measuring the levels of antibodies against pigment surface antigens, have shown that IgG- and IgM-based pigment cell antibodies were present in 80 % of active vitiligo patients. No IgG was seen among stable patients and controls, but 21 % of inactive vitiligo patients and 16 % of controls had notable levels of IgM [53]. In later studies, antibodies to MCHRl (melanin-concentrating hormone receptor 1) were found in 16.4 % of vitiligo patients, whereas no reactivity was exhibited in the control sera [54].