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

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 (p_meta-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 (p_meta-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. What's new? Only a small percentage of melanoma risk is known to be linked to genetic variants identified by genome-wide association studies. In this study, the authors sought to determine whether variants within multiple pathways might interact to increase this risk. They identified five pathways associated with melanoma, and showed significant interaction between variants at TERF1 and AFAP1L2 loci. Given the key role of TERF1 in telomere biology and its physical interaction with AFAP1L2, these results support a role for telomere dysfunction in melanoma development.