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Integrated pathway and epistasis analysis reveals interactive effect of genetic variants at TERF1 and AFAP1L2 loci on melanoma risk.

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Date
2015-10-15
Authors
Brossard, Myriam
Fang, Shenying
Vaysse, Amaury
Wei, Qingyi
Chen, Wei V
Mohamdi, Hamida
Maubec, Eve
Lavielle, Nolwenn
Galan, Pilar
Lathrop, Mark
Avril, Marie-Françoise
Lee, Jeffrey E
Amos, Christopher I
Demenais, Florence
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Abstract
Genome-wide association studies (GWASs) have characterized 13 loci associated with melanoma, which only account for a small part of melanoma risk. To identify new genes with too small an effect to be detected individually but which collectively influence melanoma risk and/or show interactive effects, we used a two-step analysis strategy including pathway analysis of genome-wide SNP data, in a first step, and epistasis analysis within significant pathways, in a second step. Pathway analysis, using the gene-set enrichment analysis (GSEA) approach and the gene ontology (GO) database, was applied to the outcomes of MELARISK (3,976 subjects) and MDACC (2,827 subjects) GWASs. Cross-gene SNP-SNP interaction analysis within melanoma-associated GOs was performed using the INTERSNP software. Five GO categories were significantly enriched in genes associated with melanoma (false discovery rate ≤ 5% in both studies): response to light stimulus, regulation of mitotic cell cycle, induction of programmed cell death, cytokine activity and oxidative phosphorylation. Epistasis analysis, within each of the five significant GOs, showed significant evidence for interaction for one SNP pair at TERF1 and AFAP1L2 loci (pmeta-int  = 2.0 × 10(-7) , which met both the pathway and overall multiple-testing corrected thresholds that are equal to 9.8 × 10(-7) and 2.0 × 10(-7) , respectively) and suggestive evidence for another pair involving correlated SNPs at the same loci (pmeta-int  = 3.6 × 10(-6) ). This interaction has important biological relevance given the key role of TERF1 in telomere biology and the reported physical interaction between TERF1 and AFAP1L2 proteins. This finding brings a novel piece of evidence for the emerging role of telomere dysfunction into melanoma development.
Type
Journal article
Subject
gene-gene interaction
genome-wide association studies
melanoma
pathway analysis
Adaptor Proteins, Signal Transducing
Epistasis, Genetic
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Melanoma
Polymorphism, Single Nucleotide
Signal Transduction
Skin Neoplasms
Telomere-Binding Proteins
Permalink
https://hdl.handle.net/10161/10671
Published Version (Please cite this version)
10.1002/ijc.29570
Publication Info
Brossard, Myriam; Fang, Shenying; Vaysse, Amaury; Wei, Qingyi; Chen, Wei V; Mohamdi, Hamida; ... Demenais, Florence (2015). Integrated pathway and epistasis analysis reveals interactive effect of genetic variants at TERF1 and AFAP1L2 loci on melanoma risk. Int J Cancer, 137(8). pp. 1901-1909. 10.1002/ijc.29570. Retrieved from https://hdl.handle.net/10161/10671.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Wei

Qingyi Wei

Professor in Population Health Sciences
Qingyi Wei, MD, PhD, Professor in the Department of Medicine, is Associate Director for Cancer Control and Population Sciences, Co-leader of CCPS and Co-leader of Epidemiology and Population Genomics (Focus Area 1). He is a professor of Medicine and an internationally recognized epidemiologist focused on the molecular and genetic epidemiology of head and neck cancers, lung cancer, and melanoma. His research focuses on biomarkers and genetic determinants for the DNA repair deficient phenotype and
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