Abstract 1297: The heritability of melanoma differs between light- and dark-skinned individuals of European descent

Abstract Melanoma is strongly associated with exposure to ultraviolet radiation (UV). The prevalence of melanoma is much higher in lighter-skinned Caucasians as compared to darker-skinned Caucasians who have a higher concentration of melanin in their skin which absorbs UV radiation and prevents it from reaching deeper layers of the skin to cause DNA damage. This suggests that the relative contributions of genes and environment in the etiology of melanoma and the genetic architecture of melanoma susceptibility may differ between these two groups. To test this hypothesis, we assessed the heritability of melanoma separately in self-reported light- and dark-skinned Caucasians using data from a previously published melanoma GWAS of 2000 cases and 1000 controls (Amos et al, 2011). Employing the GCTA method developed by Visscher et al (Yang et al, 2011), which estimates the additive genetic contributions of all genotyped single nucleotide polymorphisms (SNPs) to phenotypic variance, we observed that melanoma was highly heritable in dark-skinned Caucasians (h2 = 66%, SE = 25%, p = 0.0058), but not significantly heritable in light-skinned Caucasians (h2 = 15%, SE = 22%, p = 0.25). This suggests that whereas inherited common genetic variation contributes significantly to melanoma susceptibility in dark-skinned Caucasians, this is not the case in lighter-skinned Caucasians. To determine the consequences of this difference in heritability on melanoma risk, we investigated the enrichment of expression quantitative trait loci (eQTLs) separately in light-skinned Caucasians and dark-skinned Caucasians using a permutation-based strategy. We generated 1000 permutations of the melanoma GWAS, shuffling case-control status each time. In each of the permuted datasets, we calculated the percentage of significant disease-associated variants that are also eQTLs. Then we compared the actual percentage of GWAS hits that are eQTLs to the expected percentage under the null based on the permutations to assess whether there is a significant enrichment of functional variants in the GWAS. We found a significant enrichment of skin and lymphoblastoid cell line (LCL) eQTLs in among the melanoma-associated SNPs (p < 10-4) in the GWAS of light-skinned but not dark-skinned Caucasians. Furthermore the target genes of these eQTLs showed a functional enrichment of response pathways to ultraviolet radiation (UV), the major cause of melanoma. Taken together, these findings indicate that melanoma susceptibility not only has varying contributions of genes and environment but also different genetic architectures in light- vs dark- Caucasians. More broadly, heritability can provide important insights into variable contributions of genetics and environment to cancer and other complex diseases, and can be used to divide patients into genetically homogenous subsets to maximize power to detect significant genotype-disease associations. Citation Format: Imge Hulur, Andrew Skol, Kenan Onel. The heritability of melanoma differs between light- and dark-skinned individuals of European descent. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1297. doi:10.1158/1538-7445.AM2014-1297