SYMPHONY, an information-theoretic method for gene–gene and gene–environment interaction analysis of disease syndromes

We develop an information-theoretic method for gene–gene (GGI) and gene–environmental interactions (GEI) analysis of syndromes, defined as a phenotype vector comprising multiple quantitative traits (QTs). The K-way interaction information (KWII), an information-theoretic metric, was derived for multivariate normal distributed phenotype vectors. The utility of the method was challenged with three simulated data sets, the Genetic Association Workshop-15 (GAW15) rheumatoid arthritis data set, a high-density lipoprotein (HDL) and atherosclerosis data set from a mouse QT locus study, and the 1000 Genomes data. The dependence of the KWII on effect size, minor allele frequency, linkage disequilibrium, population stratification/admixture, as well as the power and computational time requirements of the novel method was systematically assessed in simulation studies. In these studies, phenotype vectors containing two and three constituent multivariate normally distributed QTs were used and the KWII was found to be effective at detecting GEI associated with the phenotype. High KWII values were observed for variables and variable combinations associated with the syndrome phenotype compared with uninformative variables not associated with the phenotype. The KWII values for the phenotype-associated combinations increased monotonically with increasing effect size values. The KWII also exhibited utility in simulations with non-linear dependence between the constituent QTs. Analysis of the HDL and atherosclerosis data set indicated that the simultaneous analysis of both phenotypes identified interactions not detected in the analysis of the individual traits. The information-theoretic approach may be useful for non-parametric analysis of GGI and GEI of complex syndromes.