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Meta-Analysis
. 2018 Nov 14;9(1):4774.
doi: 10.1038/s41467-018-06649-5.

Novel Pleiotropic Risk Loci for Melanoma and Nevus Density Implicate Multiple Biological Pathways

Collaborators, Affiliations
Free PMC article
Meta-Analysis

Novel Pleiotropic Risk Loci for Melanoma and Nevus Density Implicate Multiple Biological Pathways

David L Duffy et al. Nat Commun. .
Free PMC article

Erratum in

  • Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.
    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, Martin NG. Duffy DL, et al. Nat Commun. 2019 Jan 14;10(1):299. doi: 10.1038/s41467-018-08078-w. Nat Commun. 2019. PMID: 30643134 Free PMC article.

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.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Miami plot of nevus count and melanoma meta-analysis. P values where either P < 10−5. The –log10 P values for the nevus GWAS meta-analysis are above the central solid line and those for the melanoma GWAS meta-analysis are below that line. Novel nevus loci are highlighted
Fig. 2
Fig. 2
Manhattan plot of P values from meta-analysis combining nevus and melanoma results
Fig. 3
Fig. 3
Results of analyses using GWAS-PW, which assign posterior probabilities (PPA) to each of ~ 1700 genomic regions that is a a pure melanoma locus, b a pure nevus locus, c a pleiotropic nevus and melanoma loci, and d that the locus contains co-located but distinct variants for nevi and melanoma
Fig. 4
Fig. 4
Plot of nevus and melanoma association test P values for a the region around rs1640875 in GPRC5A (chr12:12.9 Mbp) illustrating symmetrical influence on nevus count and melanoma risk; note that neither univariate peaks achieve significance alone but in combination they do (see Table 2, Fig. 2), and b the region around rs7313352 in KITLG (chr12:88.6 Mbp), a “pure” nevus locus with negligible direct effect on melanoma risk
Fig. 5
Fig. 5
UCSC Genome Browser view of region near NFIC (19p13.3). The pale blue line highlights location of rs34466956, which coincides with a narrow regulatory region as seen in in the 22 short red bars indicating open chromatin in melanocytes and skin. These align in the bottom 6 tracks with narrow yellow regions indicating results of hidden Markov models summarizing the evidence from multiple experiments for open chromatin in melanocytes. An MITF ChipSeq peak also overlies this same region (gray track, GSM1517751). NFIC is expressed in melanocytes, and a second larger MITF peak overlies intron 1 in two ChipSeq experiments viz. GSE50681_MITF, see short solid black bar, and also the tall sharp gray peak below it in GSM1517751. See Supplementary Methods for details

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References

    1. Tucker MA. Melanoma epidemiology. Hematol. Oncol. Clin. North. Am. 2009;23:383–387. doi: 10.1016/j.hoc.2009.03.010. - DOI - PMC - PubMed
    1. Olsen CM, Carroll HJ, Whiteman DC. Estimating the attributable fraction for cancer: a meta-analysis of nevi and melanoma. Cancer Prev. Res (Phila.) 2010;3:233–45. doi: 10.1158/1940-6207.CAPR-09-0108. - DOI - PubMed
    1. Zhu G, et al. A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs. Am. J. Hum. Genet. 1999;65:483–492. doi: 10.1086/302494. - DOI - PMC - PubMed
    1. Wachsmuth RC, et al. Heritability and gene-environment interactions for melanocytic nevus density examined in a U.K. adolescent twin study. J. Invest Dermatol. 2001;117:348–352. doi: 10.1046/j.0022-202x.2001.01415.x. - DOI - PubMed
    1. Falchi M, et al. Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat. Genet. 2009;41:915–919. doi: 10.1038/ng.410. - DOI - PMC - PubMed

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