Empirical hierarchical bayes approach to gene-environment interactions: development and application to genome-wide association studies of lung cancer in TRICL

Genet Epidemiol. 2013 Sep;37(6):551-559. doi: 10.1002/gepi.21741. Epub 2013 Jul 26.


The analysis of gene-environment (G × E) interactions remains one of the greatest challenges in the postgenome-wide association studies (GWASs) era. Recent methods constitute a compromise between the robust but underpowered case-control and powerful case-only methods. Inferences of the latter are biased when the assumption of gene-environment (G-E) independence in controls fails. We propose a novel empirical hierarchical Bayes approach to G × E interaction (EHB-GE), which benefits from greater rank power while accounting for population-based G-E correlation. Building on Lewinger et al.'s ([2007] Genet Epidemiol 31:871-882) hierarchical Bayes prioritization approach, the method first obtains posterior G-E correlation estimates in controls for each marker, borrowing strength from G-E information across the genome. These posterior estimates are then subtracted from the corresponding case-only G × E estimates. We compared EHB-GE with rival methods using simulation. EHB-GE has similar or greater rank power to detect G × E interactions in the presence of large numbers of G-E correlations with weak to strong effects or only a low number of such correlations with large effect. When there are no or only a few weak G-E correlations, Murcray et al.'s method ([2009] Am J Epidemiol 169:219-226) identifies markers with low G × E interaction effects better. We applied EHB-GE and competing methods to four lung cancer case-control GWAS from the Interdisciplinary Research in Cancer of the Lung/International Lung Cancer Consortium with smoking as environmental factor. A number of genes worth investigating were identified by the EHB-GE approach.

Keywords: GEWIS; GWAS; lung cancer; population G-E correlation; rank power.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bayes Theorem*
  • Bias
  • Case-Control Studies
  • Computer Simulation
  • Gene-Environment Interaction*
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Lung Neoplasms / genetics*
  • Models, Genetic*
  • Smoking