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

Duffy, David L.; Martin, Nicholas G and , (2018) In Nature Communications 9(1). p.1-10
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... (More)
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. © 2018, The Author(s). (Less)
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cytochrome P450 1B1, histone deacetylase 4, interferon regulatory factor 4, peroxisome proliferator activated receptor gamma coactivator 1beta, actin binding protein, carrier protein, CYP1B1 protein, human, DOCK8 protein, human, G protein coupled receptor, GPRC5A protein, human, guanine nucleotide exchange factor, HDAC4 protein, human, histone deacetylase, interferon regulatory factor, interferon regulatory factor-4, KITLG protein, human, microRNA, MIRN146 microRNA, human, nerve protein, nuclear protein, phospholipase A2 group VI, PLA2G6 protein, human, PPARGC1B protein, human, repressor protein, RNA, stem cell factor, Stn1 protein, human, SYNE2 protein, human, telomerase, telomerase RNA, telomere binding protein, biology, cancer, gene, gene expression, meta-analysis, risk assessment, skin, Article, Australia, cutaneous melanoma, gene locus, genetic risk, genome-wide association study, human, meta analysis (topic), Netherlands, pigmented nevus, single nucleotide polymorphism, telomere homeostasis, United Kingdom, United States, Caucasian, genetic predisposition, genetics, melanoma, meta analysis, pleiotropy, skin tumor, Carrier Proteins, Cytochrome P-450 CYP1B1, European Continental Ancestry Group, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Group VI Phospholipases A2, Guanine Nucleotide Exchange Factors, Histone Deacetylases, Humans, Interferon Regulatory Factors, Melanoma, Microfilament Proteins, MicroRNAs, Nerve Tissue Proteins, Nevus, Pigmented, Nuclear Proteins, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, Repressor Proteins, Skin Neoplasms, Stem Cell Factor, Telomerase, Telomere-Binding Proteins
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Nature Communications
volume
9
issue
1
pages
1 - 10
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Nature Publishing Group
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  • pmid:30429480
  • scopus:85047573234
ISSN
2041-1723
DOI
10.1038/s41467-018-06649-5
language
English
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yes
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617e664b-c488-4e88-9fa8-65e3703c5fb2
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2019-06-05 14:11:03
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2019-07-16 04:10:58
@article{617e664b-c488-4e88-9fa8-65e3703c5fb2,
  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. © 2018, The Author(s).},
  articleno    = {4774},
  author       = {Duffy, David L. and Martin, Nicholas G and , },
  issn         = {2041-1723},
  keyword      = {cytochrome P450 1B1,histone deacetylase 4,interferon regulatory factor 4,peroxisome proliferator activated receptor gamma coactivator 1beta,actin binding protein,carrier protein,CYP1B1 protein, human,DOCK8 protein, human,G protein coupled receptor,GPRC5A protein, human,guanine nucleotide exchange factor,HDAC4 protein, human,histone deacetylase,interferon regulatory factor,interferon regulatory factor-4,KITLG protein, human,microRNA,MIRN146 microRNA, human,nerve protein,nuclear protein,phospholipase A2 group VI,PLA2G6 protein, human,PPARGC1B protein, human,repressor protein,RNA,stem cell factor,Stn1 protein, human,SYNE2 protein, human,telomerase,telomerase RNA,telomere binding protein,biology,cancer,gene,gene expression,meta-analysis,risk assessment,skin,Article,Australia,cutaneous melanoma,gene locus,genetic risk,genome-wide association study,human,meta analysis (topic),Netherlands,pigmented nevus,single nucleotide polymorphism,telomere homeostasis,United Kingdom,United States,Caucasian,genetic predisposition,genetics,melanoma,meta analysis,pleiotropy,skin tumor,Carrier Proteins,Cytochrome P-450 CYP1B1,European Continental Ancestry Group,Genetic Pleiotropy,Genetic Predisposition to Disease,Genome-Wide Association Study,Group VI Phospholipases A2,Guanine Nucleotide Exchange Factors,Histone Deacetylases,Humans,Interferon Regulatory Factors,Melanoma,Microfilament Proteins,MicroRNAs,Nerve Tissue Proteins,Nevus, Pigmented,Nuclear Proteins,Polymorphism, Single Nucleotide,Receptors, G-Protein-Coupled,Repressor Proteins,Skin Neoplasms,Stem Cell Factor,Telomerase,Telomere-Binding Proteins},
  language     = {eng},
  number       = {1},
  pages        = {1--10},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways},
  url          = {http://dx.doi.org/10.1038/s41467-018-06649-5},
  volume       = {9},
  year         = {2018},
}