Abstract
Background:
Vitiligo is a complex autoimmune disease characterized by the loss of melanocytes, leading to skin depigmentation. Despite advances in understanding its genetic and molecular basis, the precise mechanisms driving vitiligo remain elusive. Integrating multiple layers of omics data can provide a comprehensive view of disease pathogenesis and identify potential therapeutic targets.
Methods:
We first performed a genome-wide association study (GWAS) meta-analysis and druggability assessment using the latest data from FinnGen, the GWAS Catalog, and the UK Biobank. We subsequently investigated pathogenic and protective genes associated with vitiligo via summary-based Mendelian randomization (SMR) analysis across multiple eQTL and pQTL databases to construct a transcription factor regulatory network. Finally, we validated the genetically associated and causal genes identified in the previous analyses via microarray and single-cell RNA sequencing data.
Results:
The GWAS-meta analysis identified five genes with potential druggability: ERBB3, RHOH, CDK10, MC1R, and NDUFAF3. Drug target exploration and molecular docking were performed for these genes. SMR analysis revealed that five genes—CTSS, CTSH, STX8, KIR2DL3, and GRHPR—are causally associated with vitiligo at both the pQTL and eQTL levels. By integrating microarray and single-cell transcriptomic data, we detected differential expression of CTSS and its transcription factor STAT1/3 in both the blood and lesional skin of vitiligo patients.
Conclusions:
Our integrative multiomics approach provides new insights into the genetic and molecular mechanisms underlying vitiligo. The JAK/STAT pathway may contribute to vitiligo pathogenesis by regulating CTSS, which is involved in melanocyte antigen processing and presentation. Future research should focus on validating these findings and exploring the therapeutic potential of CTSS and genetically associated genes.