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

Melanoma GWAS Consortium

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Article number4774
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

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Nevi and Melanomas
loci
Nevus
Melanoma
genes
Genome-Wide Association Study
bivariate analysis
Genes
telomeres
Single Nucleotide Polymorphism
Meta-Analysis
Telomere Homeostasis
Netherlands
Pigmented Nevus
maintenance
Skin

Cite this

@article{869a1d95e893426b81731455573781b8,
title = "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.",
author = "{Melanoma GWAS Consortium} and Duffy, {David L.} and Gu Zhu and Xin Li and Marianna Sanna and Iles, {Mark M.} and Jacobs, {Leonie C.} and Evans, {David M.} and Seyhan Yazar and Jonathan Beesley and Law, {Matthew H.} and Peter Kraft and Alessia Visconti and Taylor, {John C.} and Fan Lui and Wright, {Margaret J.} and Henders, {Anjali K.} and Lisa Bowdler and Dan Glass and Ikram, {Arfan M.} and Uitterlinden, {Andr{\'e} G.} and Madden, {Pamela A.} and Heath, {Andrew C.} and Nelson, {Elliot C.} and Green, {Adele C.} and Stephen Chanock and Barrett, {Jennifer H.} and Brown, {Matthew A.} and Hayward, {Nicholas K.} and Stuart MacGregor and Sturm, {Richard A.} and Hewitt, {Alex W.} and Lee, {Jeffrey E.} and Myriam Brossard and Moses, {Eric K.} and Fengju Song and Rajiv Kumar and Easton, {Douglas F.} and Pharoah, {Paul D.P.} and Swerdlow, {Anthony J.} and Kypreou, {Katerina P.} and Mark Harland and Juliette Randerson-Moor and Akslen, {Lars A.} and Andresen, {Per A.} and Avril, {Marie Fran{\cc}oise} and Esther Azizi and Scarr{\`a}, {Giovanna Bianchi} and Brown, {Kevin M.} and Tadeusz Dębniak and Elder, {David E.} and Shenying Fang and Eitan Friedman and Pilar Galan and Paola Ghiorzo and Gillanders, {Elizabeth M.} and Goldstein, {Alisa M.} and Gruis, {Nelleke A.} and Johan Hansson and Per Helsing and Marko Hočevar and Veronica H{\"o}iom and Christian Ingvar and Kanetsky, {Peter A.} and Chen, {Wei V.} and Landi, {Maria Teresa} and Julie Lang and Lathrop, {G. Mark} and Jan Lubiński and Mackie, {Rona M.} and Mann, {Graham J.} and Anders Molven and Srdjan Novaković and H{\aa}kan Olsson and Susana Puig and Puig-Butille, {Joan Anton} and Radford-Smith, {Graham L.} and {van der Stoep}, Nienke and {van Doorn}, Remco and Whiteman, {David C.} and Craig, {Jamie E.} and Dirk Schadendorf and Simms, {Lisa A.} and Burdon, {Kathryn P.} and Nyholt, {Dale R.} and Pooley, {Karen A.} and Nicholas Orr and Stratigos, {Alexander J.} and Cust, {Anne E.} and Ward, {Sarah V.} and Schulze, {Hans Joachim} and Dunning, {Alison M.} and Florence Demenais and Amos, {Christopher I.} and Manfred Kayser and Hunter, {David J.} and {Newton Bishop}, {Julia A.} and Spector, {Timothy D.} and Montgomery, {Grant W.} and Mackey, {David A.} and Smith, {George Davey} and Nijsten, {Tamar E.} and Bishop, {D. Timothy} and Veronique Bataille and Mario Falchi and Jiali Han and Martin, {Nicholas G.}",
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Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. / Melanoma GWAS Consortium.

In: Nature Communications, Vol. 9, No. 1, 4774, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

AU - Melanoma GWAS Consortium

AU - Duffy, David L.

AU - Zhu, Gu

AU - Li, Xin

AU - Sanna, Marianna

AU - Iles, Mark M.

AU - Jacobs, Leonie C.

AU - Evans, David M.

AU - Yazar, Seyhan

AU - Beesley, Jonathan

AU - Law, Matthew H.

AU - Kraft, Peter

AU - Visconti, Alessia

AU - Taylor, John C.

AU - Lui, Fan

AU - Wright, Margaret J.

AU - Henders, Anjali K.

AU - Bowdler, Lisa

AU - Glass, Dan

AU - Ikram, Arfan M.

AU - Uitterlinden, André G.

AU - Madden, Pamela A.

AU - Heath, Andrew C.

AU - Nelson, Elliot C.

AU - Green, Adele C.

AU - Chanock, Stephen

AU - Barrett, Jennifer H.

AU - Brown, Matthew A.

AU - Hayward, Nicholas K.

AU - MacGregor, Stuart

AU - Sturm, Richard A.

AU - Hewitt, Alex W.

AU - Lee, Jeffrey E.

AU - Brossard, Myriam

AU - Moses, Eric K.

AU - Song, Fengju

AU - Kumar, Rajiv

AU - Easton, Douglas F.

AU - Pharoah, Paul D.P.

AU - Swerdlow, Anthony J.

AU - Kypreou, Katerina P.

AU - Harland, Mark

AU - Randerson-Moor, Juliette

AU - Akslen, Lars A.

AU - Andresen, Per A.

AU - Avril, Marie Françoise

AU - Azizi, Esther

AU - Scarrà, Giovanna Bianchi

AU - Brown, Kevin M.

AU - Dębniak, Tadeusz

AU - Elder, David E.

AU - Fang, Shenying

AU - Friedman, Eitan

AU - Galan, Pilar

AU - Ghiorzo, Paola

AU - Gillanders, Elizabeth M.

AU - Goldstein, Alisa M.

AU - Gruis, Nelleke A.

AU - Hansson, Johan

AU - Helsing, Per

AU - Hočevar, Marko

AU - Höiom, Veronica

AU - Ingvar, Christian

AU - Kanetsky, Peter A.

AU - Chen, Wei V.

AU - Landi, Maria Teresa

AU - Lang, Julie

AU - Lathrop, G. Mark

AU - Lubiński, Jan

AU - Mackie, Rona M.

AU - Mann, Graham J.

AU - Molven, Anders

AU - Novaković, Srdjan

AU - Olsson, Håkan

AU - Puig, Susana

AU - Puig-Butille, Joan Anton

AU - Radford-Smith, Graham L.

AU - van der Stoep, Nienke

AU - van Doorn, Remco

AU - Whiteman, David C.

AU - Craig, Jamie E.

AU - Schadendorf, Dirk

AU - Simms, Lisa A.

AU - Burdon, Kathryn P.

AU - Nyholt, Dale R.

AU - Pooley, Karen A.

AU - Orr, Nicholas

AU - Stratigos, Alexander J.

AU - Cust, Anne E.

AU - Ward, Sarah V.

AU - Schulze, Hans Joachim

AU - Dunning, Alison M.

AU - Demenais, Florence

AU - Amos, Christopher I.

AU - Kayser, Manfred

AU - Hunter, David J.

AU - Newton Bishop, Julia A.

AU - Spector, Timothy D.

AU - Montgomery, Grant W.

AU - Mackey, David A.

AU - Smith, George Davey

AU - Nijsten, Tamar E.

AU - Bishop, D. Timothy

AU - Bataille, Veronique

AU - Falchi, Mario

AU - Han, Jiali

AU - Martin, Nicholas G.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-018-06649-5

DO - 10.1038/s41467-018-06649-5

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4774

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