Population- and haplotype-dependent variation around <i>TYR</i> rs1126809: An in silico study for melanoma risk research

The common missense variant rs1126809 in the <i>TYR</i> gene, encoding a key enzyme in melanin synthesis, is linked to both albinism and melanoma susceptibility. Although its role in hypopigmentation as part of a risk haplotype is established, its function in melanoma is less understood. To investigate population- and haplotype-dependent associations surrounding <i>TYR</i> rs1126809 that may suggest directions for future studies on melanoma risk and melanocyte biology, we analyzed melanoma GWAS summary statistics using FUMA to identify lead SNPs in linkage disequilibrium with rs1126809 and assessed their regulatory potential using chromatin state data from melanocytes, keratinocytes, and fibroblasts. Haplotype structures were examined in European, American, and South Asian populations using LDlink. rs1126809 emerged as lead SNP in the <i>TYR</i> locus. Thirty SNPs were in high linkage disequilibrium, 6 of which reside in melanocyte-specific regulatory regions. These variants form population-specific haplotypes that may modulate TYR expression. In Europeans and Americans, 2 distinct haplotypes carrying the risk allele showed different linked SNP profiles, suggesting haplotype-dependent effects. The findings suggest that variations surrounding <i>TYR</i> rs1126809 may exhibit population- and haplotype-dependent patterns relevant to melanoma risk, pointing to previously unreported directions for future research and refinement of polygenic risk modeling.