Novel genes and variants associated with vitiligo: A genome-wide association and mendelian randomization meta-analysis

Summary: Abstract Body: Vitiligo is a complex autoimmune condition driven by genetic and environmental factors, with few drug targets. This study represents the largest international genome-wide association study (GWAS) of vitiligo to uncover novel genes and variants associated with vitiligo. We conducted a GWAS meta-analysis from the Million Veteran Program (MVP), FinnGen, and UK Biobank databases to identify variants significantly associated (p < 5 x 10-8) with vitiligo. Significant single nucleotide polymorphisms (SNPs) were cross-referenced with the GWAS Catalog, dbSNP, DICE, and prior GWAS studies to assess novelty. Variant-to-gene (V2G) mapping identified the most likely linked genes to these variants. To move from identifying statistical associations to inferring potential causal relationships, we performed Mendelian randomization (MR), applying a Bonferroni-corrected threshold (p < 2.96 x 10-7) based on 169,093 gene-dataset-tissue combinations. The meta-analysis included 3,134 vitiligo cases and 1,383,912 controls, identifying 51 significant GWAS signals. These signals were mapped to 43 unique candidate genes using the V2G pipeline, of which 31 had not been previously associated with vitiligo. MR analysis identified 16 putatively causal genes, including four overlapping with V2G-mapped genes (RNASET2, HLA-A, BACH2, RAB5B). Other putatively causal genes significant in MR included GDF11 (beta: -3.16, p = 7.56 x 10-9) and GABBR1 (beta: +1.57, p = 2.09 x 10-7), both of which demonstrated strong effect sizes. Higher GDF11 levels may reduce vitiligo risk by mitigating oxidative stress through reduced melanin production and improved melanocyte survival. In contrast, increased GABBR1 expression may elevate risk through immune dysregulation. These novel genetic associations enhance our understanding of the pathogenesis of vitiligo and highlight new potential genetic targets for vitiligo. Jonathan C. Hwang¹, Liana Ly¹, Bryan L. Peacker¹, Kai Gravel-Pucillo¹, Alexandre Pereira¹, Rebecca I. Hartman¹ 1. Dermatology Section, VA Boston Healthcare System, Jamaica Plain, MA, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics