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

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

United States

2015-10-07T16:26:54Z

2015-10-15

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.

http://www.ncbi.nlm.nih.gov/pubmed/25892537

1097-0215

https://hdl.handle.net/10161/10671

eng

Wiley

Int J Cancer

10.1002/ijc.29570

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

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

Journal article

Wei, Qingyi|0000-0002-3845-9445|0000-0003-4115-4439

http://www.ncbi.nlm.nih.gov/pubmed/25892537

1901

1909

8

Clinical Science Departments

Duke

Duke Cancer Institute

Institutes and Centers

Medicine

Medicine, Medical Oncology

School of Medicine

Published

137