Vitiligo is an autoimmune disease featuring destruction of melanocytes, which results in patchy depigemtation of skin and hair; two vitiligo GWAS studies identified multiple significant associations, including SNPs in 12q13.2 region. But one study ascribed the association to IKZF4 because it encodes a regulator of T cell activation and is associated with two autoimmune diseases; while the other study ascribed the association to PMEL because it encodes melanocyte protein and has the strongest differential expression between vitiligo lesions and perilesional normal skins. Here we show that vitiligo associated gene in 12q13.2 region is SUOX. Reanalyzing one GWAS dataset, we predicted tissue-specific gene-expression by leveraging Genotype-Tissue Expression (GTEx) datasets, and performed association mapping between the predicted gene-expressions and vitiligo status. SUOX expression is significantly associated with vitiligo in both Nerve (tibia) and Skin (sun exposed) tissues. Epigenetic marks encompass the most significant eQTL of SUOX in both nerve and skin tissues suggest a putative enhancer 3Kb downstream of SUOX. We silenced the putative enhancer using the CRISPR interference system and observed 50% decrease in SUOX expression in K562 cells, a cell line that has similar DNase hypersensitive sites and gene expression pattern to the skin tissue at SUOX locus. Our work provided an example to make sense GWAS hits through examining factors that affect gene expression both computationally and experimentally.

Tissue-specific Gene Expression Prediction Associates Vitiligo with SUOX through an Active Enhancer