title: Pathway, in silico and tissue-specific expression quantitative analyses of oesophageal squamous cell carcinoma genome-wide association studies data.
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.
  
  
  METHODS
  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 change = 0.69, P =  .75E-14).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, and hylandpl@mail.nih.gov.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hyland
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Yang
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Shih-Wen
authors.initials: SW
authors.lastname: Lin
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Lemin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Chaoyu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Ti
authors.initials: T
authors.lastname: Ding
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Jin-Hu
authors.initials: JH
authors.lastname: Fan
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Qiao
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Hyuna
authors.initials: H
authors.lastname: Sung
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: William
authors.initials: W
authors.lastname: Wheeler
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Carol
authors.initials: C
authors.lastname: Giffen
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdett
authors.affiliation: Division of Cancer Epidemiology and Genetics, and Division of Cancer Epidemiology and Genetics, and.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Maxwell P
authors.initials: MP
authors.lastname: Lee
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Sanford M
authors.initials: SM
authors.lastname: Dawsey
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Freedman
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Abnet
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.affiliation: Division of Cancer Epidemiology and Genetics, and.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
mesh_terms: D044466:Asian People / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics*; D002681:China; D004938:Esophageal Neoplasms / Q000235:genetics*; D000077277:Esophageal Squamous Cell Carcinoma; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015810:Linkage Disequilibrium; D016015:Logistic Models; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: Post-GWAS; SNP; eQTLs; genes; oesophageal cancer; pathways