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Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions

Barrett, Jennifer H.; Taylor, John C.; Bright, Chloe; Harland, Mark; Dunning, Alison M.; Akslen, Lars A.; Andresen, Per A.; Avril, Marie-Francoise; Azizi, Esther and Scarra, Giovanna Bianchi, et al. (2015) In International Journal of Cancer 136(6). p.1351-1360
Abstract
At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is... (More)
At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the missing heritability. What's new? In genome-wide association studies, researchers identify genetic variants that frequently associate with a particular disease, though the variants identified may not contribute to the molecular cause of the disease. This study took a closer look at 17 regions associated with melanoma, fine mapping the regions both in people with melanoma and in healthy controls. Though single SNPs account for the association in some regions, they found that in a few regions, several SNPs - and possibly multiple genes - contributed to the association signal. These findings illustrate the importance of not overlooking the interaction between multiple genetic markers when conducting such studies. (Less)
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keywords
melanoma, fine mapping, penalized regression, heritability, genome-wide, signal
in
International Journal of Cancer
volume
136
issue
6
pages
1351 - 1360
publisher
John Wiley & Sons
external identifiers
  • wos:000347705200041
  • scopus:84922262355
ISSN
0020-7136
DOI
10.1002/ijc.29099
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English
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e0098cef-d82f-4420-8d2f-7ab4ed444bcb (old id 5185994)
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2015-04-01 07:35:12
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@article{e0098cef-d82f-4420-8d2f-7ab4ed444bcb,
  abstract     = {At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the missing heritability. What's new? In genome-wide association studies, researchers identify genetic variants that frequently associate with a particular disease, though the variants identified may not contribute to the molecular cause of the disease. This study took a closer look at 17 regions associated with melanoma, fine mapping the regions both in people with melanoma and in healthy controls. Though single SNPs account for the association in some regions, they found that in a few regions, several SNPs - and possibly multiple genes - contributed to the association signal. These findings illustrate the importance of not overlooking the interaction between multiple genetic markers when conducting such studies.},
  author       = {Barrett, Jennifer H. and Taylor, John C. and Bright, Chloe and Harland, Mark and Dunning, Alison M. and Akslen, Lars A. and Andresen, Per A. and Avril, Marie-Francoise and Azizi, Esther and Scarra, Giovanna Bianchi and Brossard, Myriam and Brown, Kevin M. and Debniak, Tadeusz and Elder, David E. and Friedman, Eitan and Ghiorzo, Paola and Gillanders, Elizabeth M. and Gruis, Nelleke A. and Hansson, Johan and Helsing, Per and Hocevar, Marko and Hoiom, Veronica and Ingvar, Christian and Landi, Maria Teresa and Lang, Julie and Lathrop, G. Mark and Lubinski, Jan and Mackie, Rona M. and Molven, Anders and Novakovic, Srdjan and Olsson, Håkan and Puig, Susana and Anton Puig-Butille, Joan and van der Stoep, Nienke and van Doorn, Remco and van Workum, Wilbert and Goldstein, Alisa M. and Kanetsky, Peter A. and Pharoah, Paul D. P. and Demenais, Florence and Hayward, Nicholas K. and Newton Bishop, Julia A. and Bishop, D. Timothy and Iles, Mark M.},
  issn         = {0020-7136},
  keyword      = {melanoma,fine mapping,penalized regression,heritability,genome-wide,signal},
  language     = {eng},
  number       = {6},
  pages        = {1351--1360},
  publisher    = {John Wiley & Sons},
  series       = {International Journal of Cancer},
  title        = {Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions},
  url          = {http://dx.doi.org/10.1002/ijc.29099},
  volume       = {136},
  year         = {2015},
}