Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

David L Duffy, Gu Zhu, Xin Li, Marianna Sanna, Mark M Iles, Leonie C Jacobs, David M Evans, Seyhan Yazar, Jonathan Beesley, Matthew H Law, Peter Kraft, Alessia Visconti, John C Taylor, Fan Lui, Anjali K Henders, Lisa Bowdler, Dan Glass, Arfan M Ikram, André G Uitterlinden, Margaret J WrightPamela A Madden, Andrew C Heath, Elliot C Nelson, Adele C Green, Stephen Chanock, Jennifer H Barrett, Matthew A Brown, Nicholas K Hayward, Stuart MacGregor, Richard A Sturm, Alex W Hewitt, Melanoma GWAS Consortium, Manfred Kayser, David J Hunter, Julia A Newton Bishop, Timothy D Spector, Grant W Montgomery, David A Mackey, George Davey Smith, Tamar E Nijsten, D Timothy Bishop, Veronique Bataille, Mario Falchi, Jiali Han, Nicholas G Martin

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Abstract

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

Original languageEnglish
Pages (from-to)4774
JournalNature Communications
Volume9
Issue number1
Early online date14 Nov 2018
DOIs
Publication statusPublished - 14 Nov 2018

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