title: Genotype-environment interactions in microsatellite stable/microsatellite instability-low colorectal cancer: results from a genome-wide association study.
abstract: BACKGROUND
  Genome-wide association studies (GWAS) have led to the identification of a number of common susceptibility loci for colorectal cancer (CRC); however, none of these GWAS have considered gene-environment (G × E) interactions. Therefore, it is unclear whether current hits are modified by environmental exposures or whether there are additional hits whose effects are dependent on environmental exposures.
  
  
  METHODS
  We conducted a systematic search for G × E interactions using genome wide data from the Colon Cancer Family Registry that included 1,191 cases of microsatellite stable (MSS) or microsatellite instability-low (MSI-L) CRC and 999 controls genotyped using either the Illumina Human1M or Human1M-Duo BeadChip. We tested for interactions between genotypes and 14 environmental factors using 3 methods: a traditional case-control test, a case-only test, and the recently proposed 2-step method by Murcray and colleagues. All potentially significant findings were replicated in the ARCTIC Study.
  
  
  RESULTS
  No G × E interactions were identified that reached genome-wide significance by any of the 3 methods. When analyzing previously reported susceptibility loci, 7 significant G × E interactions were found at a 5% significance level. We investigated these 7 interactions in an independent sample and none of the interactions were replicated.
  
  
  CONCLUSIONS
  Identifying G × E interactions will present challenges in a GWAS setting. Our power calculations illustrate the need for larger sample sizes; however, as CRC is a heterogeneous disease, a tradeoff between increasing sample size and heterogeneity needs to be considered.
  
  
  CONCLUSIONS
  The results from this first genome-wide analysis of G × E in CRC identify several challenges, which may be addressed by large consortium efforts.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. janefigu@usc.edu
authors.forename: Jane C
authors.initials: JC
authors.lastname: Figueiredo
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Lewinger
authors.forename: Chi
authors.initials: C
authors.lastname: Song
authors.forename: Peter T
authors.initials: PT
authors.lastname: Campbell
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Edlund
authors.forename: Dave J
authors.initials: DJ
authors.lastname: Duggan
authors.forename: Jagadish
authors.initials: J
authors.lastname: Rangrej
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.forename: Thomas
authors.initials: T
authors.lastname: Hudson
authors.forename: Brent
authors.initials: B
authors.lastname: Zanke
authors.forename: Michelle
authors.initials: M
authors.lastname: Cotterchio
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Mark
authors.initials: M
authors.lastname: Jenkins
authors.forename: John
authors.initials: J
authors.lastname: Hopper
authors.forename: Robert
authors.initials: R
authors.lastname: Haile
authors.forename: Polly
authors.initials: P
authors.lastname: Newcomb
authors.forename: John
authors.initials: J
authors.lastname: Potter
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
mesh_terms: D002170:Canada / Q000453:epidemiology; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000209:etiology*; D004777:Environment; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D040641:Quantitative Trait Loci; D012307:Risk Factors