The genetic architecture of vitiligo

Abstract

Vitiligo is an autoimmune disease in which destruction of skin melanocytes results in patches of white skin and hair. Genome-wide linkage studies and genome-wide association studies in European ancestry cases identified over 50 vitiligo susceptibility loci, defining a model of melanocyte-directed autoimmunity. Vitiligo heritability is exceedingly high, ~2/3 coming from common and ~1/3 from rare genomic variants; ~20% of vitiligo risk is environmental. Vitiligo genetic risk is polygenic, with greater additive risk in multiplex vitiligo families than simplex cases. Vitiligo age-of-onset is bimodal, also involving a major genetic component; a MHC enhancer haplotype confers extreme risk for vitiligo (OR 8.1) and early disease onset, increasing expression of HLA-DQB1 mRNA and HLA-DQ protein and thus perhaps facilitating presentation of triggering antigens. Vitiligo triggering also involves a major environmental component; dramatic delay in vitiligo age-of-onset, especially from 1973 to 2004, suggests that exposure or response to a key vitiligo environmental trigger diminished during this period. Together, these findings provide deep understanding of vitiligo pathogenesis and genetic architecture, suggesting that vitiligo represents a tractable model for investigating complex disease genetic architecture and predictive aspects of personalized medicine.

Keywords: age-of-onset; complex disease; genetic architecture; heritability; vitiligo.

Figure 1:

An illustration of one of Thomas Addison’s two patients with both Addison’s disease and vitiligo. Reprinted from Addison’s original case report (Addison, 1855).

Figure 2:

Manhattan plot across the chromosomes of genome-wide meta-analysis results for 8,966,411 genotyped and imputed markers from three vitiligo GWAS (Jin et al., 2010, 2012, 2016) in a total 4,680 European-ancestry cases and 39,586 controls. Dotted line indicates the threshold for genome-wide significance (P < 5 × 10⁻⁸). Reprinted with from Jin et al. (2016) with permission.

Figure 3.

Fraction of total vitiligo risk attributable to the environment (orange, 20%), common genetic variants (yellow, 57%), and rare genetic variants (blue, 23%).

Figure 4.

Vitiligo polygenic risk score categorized by the number of affected relatives reported by the proband. The Y-axis represents the normalized risk score; units represent standard deviations (SD) difference from the mean risk score in controls. Horizontal lines denote the median, and the value of the mean is in red. The red line shows the fit linear regression line and the corresponding 95% confidence interval (CI) surrounds the line in gray. Boxes denote first through third quartiles. Each vertical bar extends from the box to the largest or smallest value, no farther than 1.5 times the inter-quartile range. Data beyond the vertical bars are considered outliers and are plotted individually. Reprinted from Roberts et al. (2019) with permission.

Figure 5.

Distribution of age-of-onset and corresponding finite mixture model for 4,523 European-ancestry vitiligo cases. The blue line shows the full distribution, the red line the early-onset distribution (mean 10.3, SD 5.6 years; 38.4%), and the green line the late-onset distribution (mean 34.0, SD 14.5 years; 61.6%). Reprinted from Jin et al. (2019a) with permission.

Figure 6.

Mean vitiligo age-of-onset in 4,406 unrelated European-ancestry cases by calendar year of onset 1951–2013. Circles indicate means and vertical bars 95% confidence intervals. Black segments indicate regression lines for time periods 1951–1969, 1970–2004, and 2005–2013. Reprinted from Jin et al. (2019b) with permission.