Genome-wide analysis identifies a quantitative trait locus in the MHC class II region associated with generalized vitiligo age of onset

Abstract

Generalized vitiligo is a common autoimmune disease in which acquired patchy depigmentation of skin, hair, and mucous membranes results from loss of melanocytes from involved areas. Previous genetic analyses have focused on vitiligo susceptibility, and have identified a number of genes involved in disease risk. Age of onset of generalized vitiligo also involves a substantial genetic component, but has not previously been studied systematically. In this study, we report a genome-wide association study of vitiligo age of onset in 1,339 generalized vitiligo patients, with replication in an independent cohort of 677 cases. We identified a quantitative trait locus for vitiligo age of onset in the major histocompatibility complex (MHC) class II region, located near c6orf10-BTNL2 (rs7758128; P=8.14 × 10(-11)), a region that is also associated with generalized vitiligo susceptibility. In contrast, there was no association of vitiligo age of onset with any other MHC or non-MHC loci that are associated with vitiligo susceptibility. These findings highlight the differing roles played by genes involved in vitiligo susceptibility versus vitiligo age of onset, and illustrate that genome-wide analyses can be used to identify genes involved in quantitative aspects of disease natural history, as well as disease susceptibility per se.

Figure 1. Genome-wide association results for generalized vitiligo age of onset

The genome-wide distribution of −log₁₀(P-values) from the unadjusted linear regression analysis for 520,460 polymorphic single-nucleotide polymorphisms (SNPs) that passed quality control (QC) filters in 1,339 unrelated generalized vitiligo patients is shown plotted across the chromosomes. The dotted line indicates the genome-wide significance criterion (P<5×10⁻⁸). The inset shows quantile–quantile (Q–Q) plots of the observed versus expected −log₁₀(P-values) for unadjusted linear regression statistics. The plot in red shows P-values for all 520,460 SNPs, whereas the plot in blue shows P-values excluding the 3,400 SNPs located across the extended major histocompatibility complex (MHC; chromosome 6: 25.9–33.4 Mb, genome build GRCh37).

Figure 2. Major histocompatibility complex association results from genome-wide analyses of generalized vitiligo age of onset and susceptibility

(a) Results of association analyses of the 3,400 (black dots) MHC region (chromosome 6: 25.9–33.4 Mb, genome build GRCh37) single-nucleotide polymorphisms (SNPs) with generalized vitiligo age of onset in 1,339 unrelated patients. The five top-ranked SNPs genome-wide are represented by red dots (dots representing rs28362680 and rs10947262 are too close to resolve). (b) Results of association analyses of the 3,400 (black dots) MHC region SNPs with generalized vitiligo susceptibility in 1,392 unrelated patients versus 2,629 unrelated controls (Jin et al., 2010a) using Cochran–Armitage trend tests implemented in PLINK (Purcell et al., 2007). The five top-ranked SNPs from the age of onset analysis are represented by red dots (dots representing rs28362680, rs28362683, and rs10947262 are too close to resolve). (c) A genomic map of the five top-ranked age-of-onsetassociated SNPs genome-wide. The arrows indicate gene orientations.