Dissecting age-specific genetic architecture of vitiligo through integrative Post-GWAS analysis

Vitiligo is a chronic acquired depigmentation disorder with a global prevalence of 0.5-2%. Early-onset (EO) and late-onset (LO) subtypes exhibit marked differences in clinical presentation and disease progression, yet their genetic underpinnings have not been fully elucidated.

We employed linkage disequilibrium score regression (LDSC) to quantify genetic correlation between EO and LO vitiligo, subsequently applying stratified LDSC to evaluate functional annotation and cell-type-specific heritability enrichment across immune cell populations. Multi-marker analysis of genomic annotation identified subtype-associated genes and assessed their potential biological functions and tissue-specific enrichment patterns. Summary-data-based Mendelian randomization (SMR) identified putative core targets at both transcriptional and translational levels, complemented by colocalization analysis to identify putative core targets. Expression specificity of core targets was assessed using peripheral blood single-cell databases, with spatial mapping performed via the genetically informed spatial mapping of cells for complex traits (gsMap) framework. Exploratory clinical validation employed Quantitative Reverse Transcription PCR (qRT-PCR) and Enzyme-Linked Immunosorbent Assay (ELISA )on patient blood samples.

Genetic correlation analysis revealed incomplete overlap between the two vitiligo subtypes (rg = 0.672-0.787), indicating distinct underlying genetic mechanisms for each phenotype. Stratified heritability analysis showed that LO vitiligo exhibited broader heritability distribution across regulatory elements, whereas EO concentrated in evolutionarily conserved regions. Cell-type enrichment differed significantly: EO involved T cells, dendritic cells, and natural killer (NK) cells; LO was restricted to T lymphocytes. Gene-based analysis identified 46 EO vitiligo-associated, 56 LO vitiligo-associated, and 20 shared genes, revealing subtype-specific biological functions and tissue enrichment patterns. SMR and colocalization confirmed ribonuclease T2 (RNASET2) as an EO core target and granzyme B (GZMB)/thyrotroph embryonic factor (TEF) as LO targets. These targets demonstrated subtype-specific expression in peripheral blood single cells. Spatial mapping showed EO genes enriched in mesenchymal and extracellular matrix compartments, while LO genes localized to epidermal and keratinocyte regions. Exploratory validation confirmed RNASET2 downregulation in EO patients, while GZMB and TEF decreased in LO patients.

This study reveals substantial genetic heterogeneity between age-stratified vitiligo subtypes. Through our multi-layered analytical approach, we identified subtype-specific risk genes, cellular mechanisms, and tissue microenvironmental contexts, thereby providing a molecular foundation for precision diagnostics and age-tailored therapeutic strategies in vitiligo management.