A meta-analysis approach with filtering for identifying gene-level gene-environment interactions

Genet Epidemiol. 2018 Jul;42(5):434-446. doi: 10.1002/gepi.22115. Epub 2018 Feb 11.


There is a growing recognition that gene-environment interaction (G × E) plays a pivotal role in the development and progression of complex diseases. Despite a wealth of genetic data on various complex diseases/traits generated from association and sequencing studies, detecting G × E via genome-wide analysis remains challenging due to power issues. In genome-wide G × E studies, a common strategy to improve power is to first conduct a filtering test and retain only the genetic variants that pass the filtering step for subsequent G × E analyses. Two-stage, multistage, and unified tests have been proposed to jointly consider the filtering statistics in G × E tests. However, such G × E tests based on data from a single study may still be underpowered. Meanwhile, large-scale consortia have been formed to borrow strength across studies and populations. In this work, motivated by existing single-study G × E tests with filtering and the needs for meta-analysis G × E approaches based on consortia data, we propose a meta-analysis framework for detecting gene-based G × E effects, and introduce meta-analysis-based filtering statistics in the gene-level G × E tests. Simulations demonstrate the advantages of the proposed method-the ofGEM test. We apply the proposed tests to existing data from two breast cancer consortia to identify the genes harboring genetic variants with age-dependent penetrance (i.e., gene-age interaction effects). We develop an R software package ofGEM for the proposed meta-analysis tests.

Keywords: breast cancer; filtering test; gene-environment interaction; meta-analysis.

Publication types

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

MeSH terms

  • Age Factors
  • Age of Onset
  • Breast Neoplasms / genetics
  • Computer Simulation
  • Female
  • Gene-Environment Interaction*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Models, Genetic
  • Penetrance
  • Risk Factors