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

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.
AuthorsDavid 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, 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
JournalNature communications (Nat Commun) Vol. 9 Issue 1 Pg. 4774 (11 14 2018) ISSN: 2041-1723 [Electronic] England
PMID30429480 (Publication Type: Journal Article, Meta-Analysis)
Chemical References
  • Carrier Proteins
  • DOCK8 protein, human
  • GPRC5A protein, human
  • Guanine Nucleotide Exchange Factors
  • Interferon Regulatory Factors
  • KITLG protein, human
  • MIRN146 microRNA, human
  • MicroRNAs
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • PPARGC1B protein, human
  • RNA-Binding Proteins
  • Receptors, G-Protein-Coupled
  • Repressor Proteins
  • SYNE2 protein, human
  • Stem Cell Factor
  • Stn1 protein, human
  • Telomere-Binding Proteins
  • interferon regulatory factor-4
  • telomerase RNA
  • RNA
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1B1
  • Telomerase
  • Group VI Phospholipases A2
  • PLA2G6 protein, human
  • HDAC4 protein, human
  • Histone Deacetylases
Topics
  • Carrier Proteins (genetics)
  • Cytochrome P-450 CYP1B1 (genetics)
  • Genetic Pleiotropy (genetics)
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Group VI Phospholipases A2 (genetics)
  • Guanine Nucleotide Exchange Factors (genetics)
  • Histone Deacetylases (genetics)
  • Humans
  • Interferon Regulatory Factors (genetics)
  • Melanoma (genetics)
  • MicroRNAs (genetics)
  • Microfilament Proteins (genetics)
  • Nerve Tissue Proteins (genetics)
  • Nevus, Pigmented (genetics)
  • Nuclear Proteins (genetics)
  • Polymorphism, Single Nucleotide
  • RNA (genetics)
  • RNA-Binding Proteins
  • Receptors, G-Protein-Coupled (genetics)
  • Repressor Proteins (genetics)
  • Skin Neoplasms (genetics)
  • Stem Cell Factor (genetics)
  • Telomerase (genetics)
  • Telomere-Binding Proteins (genetics)
  • White People (genetics)

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