Fine Mapping of Genetic Susceptibility Loci for Melanoma Reveals a Mixture of Single Variant and Multiple Variant Regions

Int J Cancer. 2015 Mar 15;136(6):1351-60. doi: 10.1002/ijc.29099. Epub 2014 Aug 14.

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."

Keywords: fine mapping; genome-wide signal; heritability; melanoma; penalized regression.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Mapping
  • Cyclin D1 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Humans
  • Melanoma / genetics*
  • Polymorphism, Single Nucleotide*
  • Telomerase / genetics

Substances

  • CCND1 protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin D1
  • TERT protein, human
  • Telomerase