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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Duffy, David L 
Zhu, Gu 
Li, Xin 
Sanna, Marianna 
Iles, Mark M 

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.

Description

Keywords

Carrier Proteins, Cytochrome P-450 CYP1B1, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Group VI Phospholipases A2, Guanine Nucleotide Exchange Factors, Histone Deacetylases, Humans, Interferon Regulatory Factors, Melanoma, MicroRNAs, Microfilament Proteins, Nerve Tissue Proteins, Nevus, Pigmented, Nuclear Proteins, Polymorphism, Single Nucleotide, RNA, RNA-Binding Proteins, Receptors, G-Protein-Coupled, Repressor Proteins, Skin Neoplasms, Stem Cell Factor, Telomerase, Telomere-Binding Proteins, White People

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

9

Publisher

Springer Nature
Sponsorship
Isaac Newton Trust (1307 (k))
Cancer Research Uk (None)
European Commission Horizon 2020 (H2020) Societal Challenges (634935)
Cancer Research UK (16565)