Abstract
Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility. Integrating systems biology information from model organisms, genome-wide expression data from tumor and matched normal tissue and GWAS data could help identifying DTC-associated genes, and pathways or functional networks in which they are involved. We performed data mining of GWAS data of the EPITHYR consortium (1551 cases and 1957 controls) using various pathways and protein–protein interaction (PPI) annotation databases and gene expression data from The Cancer Genome Atlas. We identified eight DTC-associated genes at known loci 2q35 (DIRC3), 8p12 (NRG1), 9q22 (FOXE1, TRMO, HEMGN, ANP32B, NANS) and 14q13 (MBIP). Using the EW_dmGWAS approach we found that gene networks related to glycogenolysis, glycogen metabolism, insulin metabolism and signal transduction pathways associated with muscle contraction were overrepresented with association signals (false discovery rate adjusted p-value < 0.05). Additionally, suggestive association of 21 KEGG and 75 REACTOME pathways with DTC indicate a link between DTC susceptibility and functions related to metabolism of cholesterol, amino sugar and nucleotide sugar metabolism, steroid biosynthesis, and downregulation of ERBB2 signaling pathways. Together, our results provide novel insights into biological mechanisms contributing to DTC risk.
Highlights
Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility
We identified a number of cis-expression quantitative trait loci (eQTL) for DIRC3, IGFBP5, NRG1, TRMO and NANS (Table 2), indicating that single nucleotide polymorphism (SNPs) at the associated loci could alter the regulation of the expression of these five genes
This is the first study on DTC susceptibility where integrative analyses of GWAS data, gene expression data in tumor, and biological pathways or physical protein–protein interaction (PPI) network data were performed to gain biological insights in the disease
Summary
Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility. We re-analyzed the genome-wide genotyping data from seven case–control studies on DTC from the EPITHYR consortium using protein–protein interaction databases, various resources for pathway maps, as well as available eQTL data on DTC from The Cancer Genome Atlas (TCGA) to annotate SNPs and to identify biological mechanisms contributing to DTC susceptibility.
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