Bivariate association analyses for the mixture of continuous and binary traits with the use of extended generalized estimating equations.

Genome-wide association (GWA) study is becoming a powerful tool in deciphering genetic basis of complex human diseases/traits. Currently, the univariate analysis is the most commonly used method to identify genes associated with a certain disease/phenotype under study. A major limitation with the univariate analysis is that it may not make use of the information of multiple correlated phenotypes, which are usually measured and collected in practical studies. The multivariate analysis has proven to be a powerful approach in linkage studies of complex diseases/traits, but it has received little attention in GWA. In this study, we aim to develop a bivariate analytical method for GWA study, which can be used for a complex situation in which continuous trait and a binary trait are measured under study. Based on the modified extended generalized estimating equation (EGEE) method we proposed herein, we assessed the performance of our bivariate analyses through extensive simulations as well as real data analyses. In the study, to develop an EGEE approach for bivariate genetic analyses, we combined two different generalized linear models corresponding to phenotypic variables using a seemingly unrelated regression model. The simulation results demonstrated that our EGEE-based bivariate analytical method outperforms univariate analyses in increasing statistical power under a variety of simulation scenarios. Notably, EGEE-based bivariate analyses have consistent advantages over univariate analyses whether or not there exists a phenotypic correlation between the two traits. Our study has practical importance, as one can always use multivariate analyses as a screening tool when multiple phenotypes are available, without extra costs of statistical power and false-positive rate. Analyses on empirical GWA data further affirm the advantages of our bivariate analytical method.