Abstract Melanoma susceptibility SNPs can be categorized by their impact on known susceptibility phenotypes (pigmentation, nevus count, telomere length, or other). In an ongoing meta-analysis of melanoma, at this stage involving 17,800 cases but soon expanding to more than 30,000 cases, 26 SNPs have achieved genome-wide significance. UK Biobank is a population-based cohort of 500,000 UK persons aged at recruitment 40-69 years; participants reported pigmentation characteristics including ease of tanning, natural hair color, skin color (in the absence of tan), and number of childhood sunburns. To conduct analyses, we separately analyzed the red hair phenotype while ordering the other hair colors from black to blond. Among the 26 SNPs from the melanoma GWAS, 15 were associated with at least one pigmentation factor assessed in UK Biobank (each at p <10-5) with 5 being associated with all pigmentation factors (e.g., SLC45A2, ASIP, MC1R) while others were associated with a subset of factors (e.g., RAD23B/TAL2 was strongly associated with hair color alone). 13 of the melanoma SNPs were associated with "ease of tanning." Detailed analysis of "ease of tanning" SNPs found 29 genome-wide significant in a subset of UK Biobank, of which 13 were associated with melanoma risk (p <0.001) but notably 4 of the SNPs showed no evidence of melanoma risk even when being among the strongest effects for "ease of tanning" and the remainder showing weaker evidence of association. For all pigmentation factors (except having red hair), the effect sizes for a SNP on melanoma risk and pigmentation were highly correlated. We examined the 26 melanoma SNPs in recent GWAS of nevus count and telomere length, and similarly observed overlaps with these phenotypes. While the telomere, nevus and pigmentation instruments were largely distinct, we found evidence of some overlap in genetic susceptibility (for instance, the PLA2G6 SNP rs2092180 is strongly associated with nevus count, ease of tanning and skin color [all p <10-12]). Combined analysis of the melanoma GWAS results with the GWAS of each of these phenotypes provides overwhelming evidence of further susceptibility loci, indicating that GWAS of intermediate phenotypes can benefit identification of the underlying genetic profile. Supported by Cancer Research UK (C588/A19167) & NIH (CA083115). This research has been conducted using the UK Biobank Resource. Citation Format: David T. Bishop, Mark M. Iles, Julia A. Newton-Bishop, Jennifer H. Barrett, Adam Trouwer, Matthew Law, Stuart MacGregor, David Duffy, Nicholas G. Martin, Nicholas Hayward, Anne Cust, Maria T. Landi, Alisa Goldstein, Jianxin Shi, Mitch Machiela, Florence Demenais, Peter Kanetsky, GenoMEL & MELANOSTRUM. Understanding melanoma susceptibility through GWAS of risk phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 234.
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