Pathway, in silico and 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, Hyuna Sung, William Wheeler, Carol Giffen, Laurie Burdett, Zhaoming Wang, Maxwell P. Lee, Stephen J. Chanock, Sanford M. DawseyNeal D. Freedman, Christian C. Abnet, Alisa M. Goldstein, Kai Yu, Philip R. Taylor

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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 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 change1/40.69, P1/46.75E-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.

Original languageEnglish (US)
Pages (from-to)206-220
Number of pages15
JournalInternational journal of epidemiology
Volume45
Issue number1
DOIs
StatePublished - Feb 1 2016

Keywords

  • EQTLs
  • Genes
  • Oesophageal cancer
  • Pathways
  • Post-GWAS
  • SNP

ASJC Scopus subject areas

  • Epidemiology

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