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

In English

Författare

  • Jennifer H. Barrett
  • John C. Taylor
  • Chloe Bright
  • Mark Harland
  • Alison M. Dunning
  • Lars A. Akslen
  • Per A. Andresen
  • Marie-Francoise Avril
  • Esther Azizi
  • Giovanna Bianchi Scarra
  • Myriam Brossard
  • Kevin M. Brown
  • Tadeusz Debniak
  • David E. Elder
  • Eitan Friedman
  • Paola Ghiorzo
  • Elizabeth M. Gillanders
  • Nelleke A. Gruis
  • Johan Hansson
  • Per Helsing
  • Marko Hocevar
  • Veronica Hoiom
  • Christian Ingvar
  • Maria Teresa Landi
  • Julie Lang
  • G. Mark Lathrop
  • Jan Lubinski
  • Rona M. Mackie
  • Anders Molven
  • Srdjan Novakovic
  • Håkan Olsson
  • Susana Puig
  • Joan Anton Puig-Butille
  • Nienke van der Stoep
  • Remco van Doorn
  • Wilbert van Workum
  • Alisa M. Goldstein
  • Peter A. Kanetsky
  • Paul D. P. Pharoah
  • Florence Demenais
  • Nicholas K. Hayward
  • Julia A. Newton Bishop
  • D. Timothy Bishop
  • Mark M. Iles
Visa allt

Summary, in English

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.

Avdelning/ar

Publiceringsår

2015

Språk

Engelska

Sidor

1351-1360

Publikation/Tidskrift/Serie

International Journal of Cancer

Volym

136

Issue

6

Dokumenttyp

Artikel i tidskrift

Förlag

John Wiley & Sons Inc.

Ämne

  • Cancer and Oncology

Nyckelord

  • melanoma
  • fine mapping
  • penalized regression
  • heritability
  • genome-wide
  • signal

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 0020-7136