A testing framework for identifying susceptibility genes in the presence of epistasis.
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).
Millstein
Joshua
J
National Oceanic and Atmospheric Administration/National Marine Fisheries Service, Alaska Fisheries Science Center, Seattle, WA 98115, USA. josh.millstein@noaa.gov
Conti
David V
DV
Gilliland
Frank D
FD
Gauderman
W James
WJ
D001741:Black or African American / Q000235:genetics; D001213:Asian / Q000235:genetics; D001249:Asthma / Q000235:genetics; D002374:Catalase / Q000235:genetics; D002648:Child; D003198:Computer Simulation; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics; D016013:Likelihood Functions; D008957:Models, Genetic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D011994:Recombinant Proteins
D007377:Interleukin-3; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C404145:myelopoietin; D016179:Granulocyte Colony-Stimulating Factor; D002374:Catalase; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human