Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
Authors: Duffy David L. , Zhu Gu , Li Xin , Sanna Marianna , Iles Mark , Jacobs Leonie C. , Evans David M. , Yazar Seyhan , Beesley Jonathan , Law Matthew , Kraft Peter , Visconti Alessia , Taylor John C. , Lui Fan , Wright Margaret J. , Henders Anjali K. , Bowdler Lisa , Glass Dan , Ikram Arfan M. , Uitterlinden André G. , Madden Pamela A. , Heath Andrew C. , Nelson Elliot C. , Green Adele C. , Chanock Stephen , Barrett Jennifer H. , Brown Matthew A. , Hayward Nicholas K. , MacGregor Stuart , Sturm Richard A. , Hewitt Alex W. ,   Melanoma GWAS Consortium, Kayser Manfred , Hunter David J. , Bishop Julia A. Newton , Spector Timothy D. , Montgomery Grant W. , Mackey David A. , Smith George Davey , Nijsten Tamar E. , Bishop D. Timothy , Bataille Veronique , Falchi Mario , Han Jiali , Martin Nicholas G. , Lee Jeffrey E. , Brossard Myriam , Moses Eric K. , Song Fengju , Kumar Rajiv , Easton Douglas F. , Pharoah Paul D. P. , Swerdlow Anthony J. , Kypreou Katerina P. , Harland Mark , Randerson-Moor Juliette , Akslen Lars A. , Andresen Per A. , Avril Marie-Françoise , Azizi Esther , Scarrà Giovanna Bianchi , Brown Kevin M. , Dębniak Tadeusz , Elder David E. , Fang Shenying , Friedman Eitan , Galan Pilar , Ghiorzo Paola , Gillanders Elizabeth M. , Goldstein Alisa M. , Gruis Nelleke A. , Hansson Johan , Helsing Per , Hočevar Marko , Höiom Veronica , Ingvar Christian , Kanetsky Peter A. , Chen Wei V. , Landi Maria Teresa , Lang Julie , Lathrop G. Mark , Lubiński Jan , Mackie Rona M. , Mann Graham J. , Molven Anders , Novaković Srdjan , Olsson Håkan , Puig Susana , Puig-Butille Joan Anton , Li Xin , L. Radford-Smith Graham , van der Stoep Nienke , van Doorn Remco , Whiteman David C. , Craig Jamie E. , Schadendorf Dirk , Simms Lisa A. , Burdon Kathryn P. , Nyholt Dale R. , Pooley Karen A. , Orr Nicholas , Stratigos Alexander J. , Cust Anne E. , Ward Sarah V. , Schulze Hans-Joachim , Dunning Alison M. , Demenais Florence , Amos Christopher I. 
Published: August 2017

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 includingMTAP,PLA2G6, andIRF4, and detect novel SNPs at a genome-wide level of significance inKITLG,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 nearGPRC5A,CYP1B1,PPARGC1B,HDAC4,FAM208BandSYNE2reached global significance, and other loci, includingMIR146AandOBFC1, reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk (KITLGan exception), while many melanoma risk loci do not alter nevus count. For example, variants inTERCandOBFC1affect 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.