Abstract
Vitiligo is a multifactorial polygenic disorder, characterized by acquired depigmented skin and overlying hair resulting from the destruction of melanocytes. Genome-wide association studies (GWASs) of vitiligo have identified approximately 100 genetic variants. However, the identification of functional genes and their regulatory elements remains a challenge. To prioritize putative functional genes and DNAm sites, we performed a Summary data-based Mendelian Randomization (SMR) and heterogeneity in dependent instruments (HEIDI) test to integrate omics summary statistics from GWAS, expression quantitative trait locus (eQTL), and methylation quantitative trait loci (meQTL) analysis of large sample size. By integrating omics data, we identified two newly putative functional genes (SPATA2L and CDK10) associated with vitiligo and further validated CDK10 by qRT-PCR in independent samples. We also identified 17 vitiligo-associated DNA methylation (DNAm) sites in Chr16, of which cg05175606 was significantly associated with the expression of CDK10 and vitiligo. Colocalization analyses detected transcript of CDK10 in the blood and skin colocalizing with cg05175606 at single nucleotide polymorphism (SNP) rs77651727. Our findings revealed that a shared genetic variant rs77651727 alters the cg05175606 as well as up-regulates gene expression of CDK10 and further decreases the risk of vitiligo.
Highlights
Vitiligo is an autoimmune disease characterized by acquired depigmented skin and overlying hair, with a prevalence of approximately 0.4% in the European population (Zhang et al, 2016)
Using summary-level genome-wide association studies (GWASs) data from the large-scale metaanalysis of vitiligo described above, we firstly conducted the SMR analysis to test for associations of vitiligo with gene expression probes by integrating vitiligo GWAS and each of the five eQTL data (Westra eQTL, CAGE eQTL, and three GTEx eQTL)
Genes were reported by previous vitiligo GWAS studies and the other genes were distant from the top GWAS associated variants
Summary
Vitiligo is an autoimmune disease characterized by acquired depigmented skin and overlying hair, with a prevalence of approximately 0.4% in the European population (Zhang et al, 2016). It is reported that patients with vitiligo are associated with multiple comorbid autoimmune diseases and have a reduced risk of several tumors including melanoma, non-melanoma skin cancer, and internal malignancies (Paradisi et al, 2014; Dahir and Thomsen, 2018; Bae et al, 2019). Vitiligo is a multifactorial disease involved in both genetic and environmental factors. Many genetic studies (such as candidate gene analyses, linkage studies, etc.) have been performed to identify genetic factors for vitiligo. Since 2008, genome-wide association studies (GWASs) have been applied in vitiligo and discovered approximately 100 genetic variants according to the GWAS catalog
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