A testing framework for identifying susceptibility genes in the presence of epistasis

Am J Hum Genet. 2006 Jan;78(1):15-27. doi: 10.1086/498850. Epub 2005 Nov 11.


An efficient testing strategy called the "focused interaction testing framework" (FITF) was developed to identify susceptibility genes involved in epistatic interactions for case-control studies of candidate genes. In the FITF approach, likelihood-ratio tests are performed in stages that increase in the order of interaction considered. Joint tests of main effects and interactions are performed conditional on significant lower-order effects. A reduction in the number of tests performed is achieved by prescreening gene combinations with a goodness-of-fit chi2 statistic that depends on association among candidate genes in the pooled case-control group. Multiple testing is accounted for by controlling false-discovery rates. Simulation analysis demonstrated that the FITF approach is more powerful than marginal tests of candidate genes. FITF also outperformed multifactor dimensionality reduction when interactions involved additive, dominant, or recessive genes. In an application to asthma case-control data from the Children's Health Study, FITF identified a significant multilocus effect between the nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase gene (NQO1), myeloperoxidase gene (MPO), and catalase gene (CAT) (unadjusted P = .00026), three genes that are involved in the oxidative stress pathway. In an independent data set consisting primarily of African American and Asian American children, these three genes also showed a significant association with asthma status (P = .0008).

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • African Americans / genetics
  • Asian Americans / genetics
  • Asthma / genetics
  • Catalase / genetics
  • Child
  • Computer Simulation
  • Epistasis, Genetic*
  • Genetic Predisposition to Disease*
  • Genetic Testing / methods*
  • Granulocyte Colony-Stimulating Factor / genetics
  • Humans
  • Interleukin-3 / genetics
  • Likelihood Functions
  • Models, Genetic*
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • Recombinant Fusion Proteins / genetics
  • Recombinant Proteins


  • Interleukin-3
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • myelopoietin
  • Granulocyte Colony-Stimulating Factor
  • Catalase
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human