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.

Metadata

Item Type:	Article
Authors/Creators:	Duffy, DL Zhu, G Li, X Sanna, M Iles, MM https://orcid.org/0000-0002-2603-6509 Jacobs, LC Evans, DM Yazar, S Beesley, J Law, MH Kraft, P Visconti, A Taylor, JC https://orcid.org/0000-0002-2518-5799 Lui, F Wright, MJ Henders, AK Bowdler, L Glass, D Ikram, AM Uitterlinden, AG Madden, PA Heath, AC Nelson, EC Green, AC Chanock, S Barrett, JH https://orcid.org/0000-0002-1720-7724 Brown, MA Hayward, NK MacGregor, S Sturm, RA Hewitt, AW Melanoma GWAS Consortium Kayser, M Hunter, DJ Newton Bishop, JA Spector, TD Montgomery, GW Mackey, DA Smith, GD Nijsten, TE Bishop, DT https://orcid.org/0000-0002-8752-8785 Bataille, V Falchi, M Han, J Martin, NG
Copyright, Publisher and Additional Information:	© 2018, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 13 September 2018 Published (online): 14 November 2018 Published: December 2018
Institution:	The University of Leeds
Funding Information:	Funder Grant number National Institute of Health - NIH (PHS) 10-17751-99-01-G5 Cancer Research UK c588/A19167
Depositing User:	Symplectic Publications
Date Deposited:	27 Nov 2018 15:14
Last Modified:	25 Jun 2023 21:37
Status:	Published
Publisher:	Springer Nature
Identification Number:	10.1038/s41467-018-06649-5
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:139190

Commentary/Response Threads

Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Lui, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, AM, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Melanoma GWAS Consortium, Kayser, M, Hunter, DJ, Newton Bishop, JA, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J and Martin, NG Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. (deposited 27 Nov 2018 15:14) [Currently Displayed]
- Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Liu, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, MA, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Melanoma GWAS Consortium, Kayser, M, Hunter, DJ, Newton Bishop, JA, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J and Martin, NG Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. (deposited 23 Feb 2022 10:01)

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