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

By David L. Duffy, Gu Zhu, Xin Li, Marianna Sanna, Mark Iles, Leonie C. Jacobs, David M Evans, Seyhan Yazar, Jonathan Beesley, Matthew Law, Peter Kraft, Alessia Visconti, John C. Taylor, Fan Lui, Margaret J Wright, Anjali K. Henders, Lisa Bowdler, Dan Glass, Arfan M. Ikram, André G. Uitterlinden, Pamela 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 Mackey, George Davey Smith, Tamar E. Nijsten, D. Timothy Bishop, Veronique Bataille, Mario Falchi, Jiali Han, Nicholas G Martin, Jeffrey E. Lee, Myriam Brossard, Eric K. Moses, Fengju Song, Rajiv Kumar, Douglas F. Easton, Paul Pharoah, Anthony J. Swerdlow, Katerina P. Kypreou, Mark Harland, Juliette Randerson-Moor, Lars A. Akslen, Per A. Andresen, Marie-Françoise Avril, Esther Azizi, Giovanna Bianchi Scarrà, Kevin M Brown, Tadeusz Dębniak, David E. Elder, Shenying Fang, Eitan Friedman, Pilar Galan, Paola Ghiorzo, Elizabeth M. Gillanders, Alisa M Goldstein, Nelleke A. Gruis, Johan Hansson, Per Helsing, Marko Hočevar, Veronica Höiom, Christian Ingvar, Peter A. Kanetsky, Wei V. Chen, Maria Teresa Landi, Julie Lang, G. Mark Lathrop, Jan Lubiński, Rona M. Mackie, Graham J. Mann, Anders Molven, Srdjan Novaković, Håkan Olsson, Susana Puig, Joan Anton Puig-Butille, Graham L. Radford-Smith, Nienke van der Stoep, Remco van Doorn, David C. Whiteman, Jamie E Craig, Dirk Schadendorf, Lisa A. Simms, Kathryn P Burdon, Dale R Nyholt, Karen A. Pooley, Nicholas Orr, Alexander J. Stratigos, Anne E. Cust, Sarah V. Ward, Hans-Joachim Schulze, Alison M Dunning, Florence Demenais, Christopher Amos

Posted 07 Aug 2017
bioRxiv DOI: 10.1101/173112 (published DOI: 10.1038/s41467-018-06649-5)

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, United Kingdom, and United States, comprising a total of 52,506 phenotyped individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs at a genome-wide level of significance in KITLG, DOCK8, and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level of significance. 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 via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.

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