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 Lui; Anjali K Henders; Lisa Bowdler; Dan Glass; Arfan M Ikram; André G Uitterlinden; Margaret J Wright; 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

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 Lui, Anjali K Henders, Lisa Bowdler, Dan Glass, Arfan M Ikram, André G Uitterlinden, Margaret J WrightPamela 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

Twin Research & Genetic Epidemiology

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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
Pages (from-to)	4774
Journal	Nature Communications
Volume	9
Issue number	1
Early online date	14 Nov 2018
DOIs	https://doi.org/10.1038/s41467-018-06649-5
Publication status	Published - 14 Nov 2018

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10.1038/s41467-018-06649-5Licence: CC BY

Novel pleiotropic risk loci_DUFFY_Accepted 30 September 2018_ GOLD VoR( CC BY)Final published version, 1.65 MBLicence: CC BY

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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., Lui, F., Henders, A. K., Bowdler, L., Glass, D., Ikram, A. M., Uitterlinden, A. G., ... Martin, N. G. (2018). Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. Nature Communications, 9(1), 4774. https://doi.org/10.1038/s41467-018-06649-5

@article{2a85c2bb32dc42e89ffb25198fc7bfaa,

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 = "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 Henders, {Anjali K} and Lisa Bowdler and Dan Glass and Ikram, {Arfan M} and Uitterlinden, {Andr{\'e} G} and Wright, {Margaret J} 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 {Melanoma GWAS Consortium} 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",

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

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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, Henders, AK, Bowdler, L, Glass, D, Ikram, AM, Uitterlinden, AG, Wright, MJ, 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 & Martin, NG 2018, 'Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways', Nature Communications, vol. 9, no. 1, pp. 4774. https://doi.org/10.1038/s41467-018-06649-5

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 - Lui, Fan

AU - Henders, Anjali K

AU - Bowdler, Lisa

AU - Glass, Dan

AU - Ikram, Arfan M

AU - Uitterlinden, André G

AU - Wright, Margaret J

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 - Melanoma GWAS Consortium

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.

U2 - 10.1038/s41467-018-06649-5

DO - 10.1038/s41467-018-06649-5

M3 - Article

C2 - 30429480

SN - 2041-1723

VL - 9

SP - 4774

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

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