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; Elliot C. Nelson; Andrew C. Heath; 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; Jamie E. Craig; Kathryn P. Burdon; 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

doi:10.1038/s41467-018-06649-5

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. UitterlindenPamela A. Madden, Elliot C. Nelson, Andrew C. Heath, 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, Jamie E. Craig, Kathryn P. Burdon, 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

College of Medicine and Public Health

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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 language	English
Article number	4774
Number of pages	10
Journal	Nature Communications
Volume	9
DOIs	https://doi.org/10.1038/s41467-018-06649-5 https://doi.org/10.1038/s41467-018-08078-w
Publication status	Published - 14 Nov 2018

Keywords

pleiotropic risk
melanocytic nevus
Meta-analysis
melanoma risk
nevogenesis pathways
gene variation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Duffy, D. L., Zhu, G., Li, X., Sanna, M., Iles, M. M., Jacobs, L. C., Evans, D. M., Yazar, S., Beesley, J., Law, M. H., Kraft, P., Visconti, A., Taylor, J. C., Liu, F., Wright, M. J., Henders, A. K., Bowdler, L., Glass, D., Ikram, M. A., ... Martin, N. G. (2018). Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. Nature Communications, 9, Article 4774. https://doi.org/10.1038/s41467-018-06649-5, https://doi.org/10.1038/s41467-018-08078-w

@article{883bc1617cd14fc29defefed06006057,

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.",

keywords = "pleiotropic risk, melanocytic nevus, Meta-analysis, melanoma risk, nevogenesis pathways, gene variation",

author = "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 Liu and Wright, {Margaret J.} and Henders, {Anjali K.} and Lisa Bowdler and Dan Glass and Ikram, {M. Arfan} and Uitterlinden, {Andr{\'e} G.} and Madden, {Pamela A.} and Nelson, {Elliot C.} and Heath, {Andrew 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 {Melanoma GWAS Consortium} 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{\c c}oise} and Esther Azizi and Scarr{\`a}, {Giovanna Bianchi} and Brown, {Kevin M.} and Tadeusz D{\c e}bniak 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 Ho{\v c}evar 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 Lubi{\'n}ski and Mackie, {Rona M.} and Mann, {Graham J.} and Anders Molven and Srdjan Novakovi{\'c} 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.}",

year = "2018",

month = nov,

day = "14",

doi = "10.1038/s41467-018-06649-5",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature",

}

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, Nelson, EC, Heath, AC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Melanoma GWAS Consortium, Craig, JE, Burdon, KP, 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 & Martin, NG 2018, 'Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways', Nature Communications, vol. 9, 4774. https://doi.org/10.1038/s41467-018-06649-5, https://doi.org/10.1038/s41467-018-08078-w

TY - JOUR

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

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 - Liu, Fan

AU - Wright, Margaret J.

AU - Henders, Anjali K.

AU - Bowdler, Lisa

AU - Glass, Dan

AU - Ikram, M. Arfan

AU - Uitterlinden, André G.

AU - Madden, Pamela A.

AU - Nelson, Elliot C.

AU - Heath, Andrew 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 - Melanoma GWAS Consortium

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 - 2018/11/14

Y1 - 2018/11/14

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.

KW - pleiotropic risk

KW - melanocytic nevus

KW - Meta-analysis

KW - melanoma risk

KW - nevogenesis pathways

KW - gene variation

UR - http://www.scopus.com/inward/record.url?scp=85047573234&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-06649-5

DO - 10.1038/s41467-018-06649-5

M3 - Article

C2 - 30643134

AN - SCOPUS:85047573234

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 4774

ER -

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

Abstract

Keywords

UN SDGs

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