Vitiligo-associated variants and genes beyond immune-related loci: A genome-wide association and Mendelian...

Although past genome-wide association studies (GWAS) have identified over 50 susceptible loci associated with vitiligo risk, few have systematically explored causality among potentially associated variants and genes. To address this, we analyzed summary statistics from 3 large-scale genomic resources, including the Million Veteran Program, United Kingdom Biobank, and FinnGen. Cases were defined using ICD-9 code 709.01 or ICD-10 code L80, including all studies that contributed genome-wide summary statistics and limiting analyses to loci with ≥1 common variant (minor allele frequency ≥1%). METAL was used to conduct a fixed effects inverse variance-weighted meta-analysis with kinship adjustment. Variant-to-gene (V2G) mapping was performed using the Open Targets V2G framework. Potentially causal effects were assessed using two-sample Mendelian randomization (MR) and genome-wide significant protein and expression quantitative trait locus instruments across 16 datasets. Genome-wide significance was defined as P < 5 x 10^-8. Among 3,134 vitiligo cases and 1,383,912 controls, 5,482 genome-wide significant variants were identified, mapping to 23 distinct loci. MR found 18 potentially causative genes, 5 of which had not been previously associated with vitiligo: GDF11, ACO2, MEI1, OR2W1-AS1, GABBR1. To our knowledge, this study identifies several previously unreported potentially causal variants and genes associated with vitiligo, as well as pathogenic pathways beyond autoimmunity.