Pathway,in silicoand tissue-specific expression quantitative analyses of oesophageal squamous cell carcinoma genome-wide association studies data

Paula L Hyland, Han Zhang, Qi Yang, Howard H Yang, Nan Hu, Shih-Wen Lin, Hua Su, Lemin Wang, Chaoyu Wang, Ti Ding, Jin-Hu Fan, You-Lin Qiao (+13 others)
2015 International Journal of Epidemiology  
Oesophageal cancer is the fourth leading cause of cancer death in China where essentially all cases are histologically oesophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses of genome-wide association study (GWAS) data combined with tissue-specific expression quantitative trait loci (eQTL) analysis and publicly available functional data can identify biological pathways and/or genes enriched with functionally-relevant disease-associated variants. Method: We used the adaptive
more » ... multilocus joint test to analyse 1827 pathways containing 6060 genes using GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. We examined the function of risk alleles using in silico and eQTL analyses in oesophageal tissues. Results: Associations with ESCC risk were observed for 36 pathways predominantly involved in apoptosis, cell cycle regulation and DNA repair and containing known GWAS-associated genes. After excluding genes with previous GWAS signals, candidate pathways (and genes) for ESCC risk included taste transduction (KEGG_hsa04742; TAS2R13, TAS2R42, TAS2R14, TAS2R46,TAS2R50), long-patch base excision repair (Reactome_pid; POLD2) and the metabolics pathway (KEGG_hsa01100; MTAP, GAPDH, DCTD, POLD2, AMDHD1). We identified and validated CASP8 rs13016963 and IDH2 rs11630814 as eQTLs, and CASP8 rs3769823 and IDH2 rs4561444 as the potential functional variants in high-linkage disequilibrium with these single nucleotide polymorphisms (SNPs), respectively. Further, IDH2 mRNA levels were down-regulated in ESCC (tumour:normal-fold change ¼ 0.69, P ¼ 6. 75E-14). Conclusion: Agnostic pathway-based analyses and integration of multiple types of functional data provide new evidence for the contribution of genes in taste transduction and metabolism to ESCC susceptibility, and for the functionality of both established and new ESCC risk-related SNPs. Key Messages • We carried out an agnostic evaluation of variants in functionally-related genes in established biological pathways and examined tissue-specific expression quantitative trait loci (eQTLs) to provide evidence of functionality and identify true risk variants. • From 1827 biological pathways and 6600 genes, we found new evidence linking genes in bitter taste transduction, long-patch base excision repair and metabolics pathways with risk of ESCC in Han Chinese. • We identified eQTL relations for CASP8 (a gene previously-associated with ESCC) in apoptotic pathways, and IDH2 (a gene not previously-associated with ESCC) in the metabolics pathway. • Although rs13016963 is the strongest CASP8 SNP in GWAS and in this study, eQTL analyses indicated that the highly correlated rs3769823 is more functionally relevant, as it locates to a secondary CASP8 promoter and has the potential to interact with the transcriptional regulator HDAC2. • Further, whereas rs11630814 was the top SNP in IDH2, the correlated rs4561444, eQTL, locates to an active enhancer in oesophageal tissue, whereby changes in IDH2 expression/production may attenuate the neutralization of reactive oxygen species and TET2-dependent demethylation of DNA. • The identification of predisposing genetic factors in genes and pathways as well as functional variants associated with ESCC development may ultimately lead to new diagnostic, prognostic and therapeutic strategies in high-risk populations. • The possible involvement of HDAC2 in the transcriptional regulation of CASP8, and IDH2 in the 5-hydroxymethylcytosine generating pathway, suggest potential for targeted epigenetic therapies.
doi:10.1093/ije/dyv294 pmid:26635288 pmcid:PMC4881832 fatcat:nhd42anierhvva52rkivaanrmy