Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

Vitiligo is an autoimmune disease in which depigmented skin results from destruction of skin melanocytes, with strong epidemiologic association with several other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1, GWAS2), we identified 27 vitiligo susceptibility loci in patients of European (EUR) ancestry. We carried out a third GWAS (GWAS3) of vitiligo in EUR subjects, with augmentation of GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three vitiligo GWAS, followed by an independent replication study. The combined analyses, with 4,680 vitiligo cases and 39,586 controls, identified 23 novel replicated loci, as well as 7 new suggestive loci, most encoding immune regulators, apoptotic regulators, and melanocyte regulators, several of which are also associated with other autoimmune diseases. Functional analyses indicate a predominance of causal regulatory variation, in some cases corresponding to eQTL at these loci. Together, the identified genes provide a framework for vitiligo genetic architecture and pathobiology, highlight genetic relationships to other autoimmune diseases and melanoma, and offer potential targets for vitiligo treatment.