Genome-wide association analysis and multi-omic Mendelian randomization study exploring the immune response in vitiligo

The etiology of vitiligo involves immune dysregulation, though its precise genetic underpinnings remain incompletely understood. Here, we employ a multi-omics approach, integrating genome-wide association studies (GWAS) and Mendelian randomization (MR), to investigate the association between immune response-related genes and vitiligo. We conducted a comprehensive meta-analysis of three GWAS encompassing generalized vitiligo cohorts from Jin et al., the FinnGen cohort, and the UK Biobank to identify novel genetic determinants of vitiligo susceptibility. Using the results from this meta-analysis, we employed Mendelian randomization (MR) and summary data-based MR (SMR) to discern immune response genes having a putative causal relationship with vitiligo on the level of plasma proteome. Additionally, we integrated summary data on immune response methylation and expression abundance levels for multi-omics validation. Further exploration involved assessing the differential abundance of immune response genes at the single-cell transcriptomic level and tracking their expression dynamics during cellular differentiation. Our meta-analysis unveiled 25 genome-wide significant vitiligo risk variants, six of which were previously unreported. Notably, the predicted protein levels of eight genes displayed associations with vitiligo, encompassing the methylation levels of CD160 and TYRO3, as well as the gene expression level of CD160. These genes were predominantly expressed in T cells and mononuclear phagocytes within vitiligo skin lesions, exhibiting distinct expression patterns and temporal changes across various disease states. Through the integration of GWAS and multi-omics MR approaches, this study identifies several immune response genes implicated in vitiligo pathogenesis, offering promising targets for future therapeutic and preventive strategies.