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Pathway-based analysis of a melanoma genome-wide association study : analysis of genes related to tumour-immunosuppression

Schoof, Nils; Iles, Mark M; Bishop, D Timothy; Newton-Bishop, Julia A; Barrett, Jennifer H and , (2011) In PLoS One 6(12).
Abstract

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539... (More)

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (p(emp)=0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (p(emp)=0.006) and secretion of suppressive factors (p(emp)=0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Immunosuppression, Melanoma, Polymorphism, Single Nucleotide
in
PLoS One
volume
6
issue
12
publisher
Public Library of Science
external identifiers
  • Scopus:84455172956
ISSN
1932-6203
DOI
10.1371/journal.pone.0029451
language
English
LU publication?
no
id
049e1adf-99d8-4075-871f-87a12e50265d
date added to LUP
2016-09-18 12:05:20
date last changed
2017-01-01 08:34:01
@article{049e1adf-99d8-4075-871f-87a12e50265d,
  abstract     = {<p>Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (p(emp)=0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (p(emp)=0.006) and secretion of suppressive factors (p(emp)=0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges.</p>},
  articleno    = {e29451},
  author       = {Schoof, Nils and Iles, Mark M and Bishop, D Timothy and Newton-Bishop, Julia A and Barrett, Jennifer H and , },
  issn         = {1932-6203},
  keyword      = {Genetic Predisposition to Disease,Genome-Wide Association Study,Humans,Immunosuppression,Melanoma,Polymorphism, Single Nucleotide},
  language     = {eng},
  number       = {12},
  publisher    = {Public Library of Science},
  series       = {PLoS One},
  title        = {Pathway-based analysis of a melanoma genome-wide association study : analysis of genes related to tumour-immunosuppression},
  url          = {http://dx.doi.org/10.1371/journal.pone.0029451},
  volume       = {6},
  year         = {2011},
}