Abstract
Background and objectives
Pigmentary traits (skin, hair, eye colour, tanning response) are epidemiologically linked to skin and ocular cancers, but the extent and nature of shared genetic architecture remain incompletely defined. In this study we explored to what extent pigmentation- and cancer-associated variants exhibit pleiotropy.
Methodology
We analysed GWAS summary statistics from European populations for skin colour; hair colour (blonde, light brown, red, dark brown, black); eye colour; tanning response; and four cancers: cutaneous malignant melanoma (CMM), basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and uveal melanoma (UM). Genetic correlations were estimated with LDSC. Multi-trait and pairwise pleiotropy were tested with CPASSOC. We reviewed available colocalization data (COLOC framework) and post-association functional annotation/mapping (e.g., FUMA) to interpret shared signals.
Results
Significant genetic correlations were observed between multiple pigmentary traits and each cancer. Multi-trait and pairwise analyses identified numerous shared regions, including canonical pigmentation loci (MC1R, ASIP, TYR, BNC2, IRF4, OCA2/HERC2, SLC24A4, DCT, TYRP1). Directions of effect indicated that lighter skin, hair and iris pigmentation and poor tanning were associated with increased risk across cancers. Colocalization data supported shared causal variants at several loci; for UM, variants driving light eye colour at IRF4 and HERC2 were linked to higher risk.
Conclusions and implications
Skin and ocular melanomas illustrate evolutionary mismatch: variants favoured at high latitudes for lighter pigmentation now elevate cancer risk under modern UV exposure. Mapping shared architecture highlights biological pathways that may refine risk prediction, motivate functional studies and inform prevention strategies.
