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 Liu, Margaret J. Wright, Anjali K. Henders, Lisa Bowdler, Dan Glass, M. Arfan 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, 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 and Nicholas G. Martin
Additional contact information
David L. Duffy: QIMR Berghofer Medical Research Institute
Gu Zhu: QIMR Berghofer Medical Research Institute
Xin Li: Indiana University
Marianna Sanna: St Thomas Hospital Campus, Kings College
Mark M. Iles: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds
Leonie C. Jacobs: University Medical Centre Rotterdam
David M. Evans: University of Bristol
Seyhan Yazar: University of Western Australia and the Lions Eye Institute
Jonathan Beesley: QIMR Berghofer Medical Research Institute
Matthew H. Law: QIMR Berghofer Medical Research Institute
Peter Kraft: Harvard T.H. Chan School of Public Health
Alessia Visconti: St Thomas Hospital Campus, Kings College
John C. Taylor: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds
Fan Liu: University Medical Centre Rotterdam
Margaret J. Wright: QIMR Berghofer Medical Research Institute
Anjali K. Henders: QIMR Berghofer Medical Research Institute
Lisa Bowdler: QIMR Berghofer Medical Research Institute
Dan Glass: St Thomas Hospital Campus, Kings College
M. Arfan Ikram: Erasmus MC
André G. Uitterlinden: Erasmus MC
Pamela A. Madden: Washington University School of Medicine
Andrew C. Heath: Washington University School of Medicine
Elliot C. Nelson: Washington University School of Medicine
Adele C. Green: QIMR Berghofer Medical Research Institute
Stephen Chanock: National Cancer Institute
Jennifer H. Barrett: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds
Matthew A. Brown: University of Queensland Diamantina Institute, Translational Research Institute
Nicholas K. Hayward: QIMR Berghofer Medical Research Institute
Stuart MacGregor: QIMR Berghofer Medical Research Institute
Richard A. Sturm: University of Queensland Diamantina Institute, Translational Research Institute
Alex W. Hewitt: University of Western Australia and the Lions Eye Institute
Manfred Kayser: University Medical Centre Rotterdam
David J. Hunter: Harvard T.H. Chan School of Public Health
Julia A. Newton Bishop: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds
Timothy D. Spector: St Thomas Hospital Campus, Kings College
Grant W. Montgomery: QIMR Berghofer Medical Research Institute
David A. Mackey: University of Western Australia and the Lions Eye Institute
George Davey Smith: University of Bristol
Tamar E. Nijsten: University Medical Centre Rotterdam
D. Timothy Bishop: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds
Veronique Bataille: St Thomas Hospital Campus, Kings College
Mario Falchi: St Thomas Hospital Campus, Kings College
Jiali Han: Indiana University
Nicholas G. Martin: QIMR Berghofer Medical Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06649-5

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