Fine-mapping of melanoma-associated genomic regions identifies novel causal SNPs in the MTAP/CDKN2A and CASP8 loci

A number of genomic regions have been associated with melanoma risk through genome-wide association studies, however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1,977 British melanoma cases and 754 controls. Variant filtering followed by Fisher's exact test analyses identified 88 variants associated with melanoma risk. Sequential conditional logistic regressions identified the distinct haplotypes on which variants lie, and massively parallel reporter assays (MPRA) provided biological insights into how these variants influence gene function. We performed further analyses to link variants to melanoma risk phenotypes and assess their association with melanoma-specific survival. Our analyses replicate previously known associations in the MC1R and TYR loci, while identifying novel potentially causal variants at the MTAP/CDKN2A and CASP8 loci. These results increase our understanding of the architecture of melanoma risk and outcome.