Inferring causal phenotype networks using structural equation models.

Phenotypic traits may exert causal effects between them. For example, on the one hand, high yield in dairy cows may increase the liability to certain diseases and, on the other hand, the incidence of a disease may affect yield negatively. Likewise, the transcriptome may be a function of the reproductive status in mammals and the latter may depend on other physiological variables. Knowledge of phenotype networks describing such interrelationships can be used to predict the behavior of complex systems, e.g. biological pathways underlying complex traits such as diseases, growth and reproduction. Structural Equation Models (SEM) can be used to study recursive and simultaneous relationships among phenotypes in multivariate systems such as genetical genomics, system biology, and multiple trait models in quantitative genetics. Hence, SEM can produce an interpretation of relationships among traits which differs from that obtained with traditional multiple trait models, in which all relationships are represented by symmetric linear associations among random variables, such as covariances and correlations. In this review, we discuss the application of SEM and related techniques for the study of multiple phenotypes. Two basic scenarios are considered, one pertaining to genetical genomics studies, in which QTL or molecular marker information is used to facilitate causal inference, and another related to quantitative genetic analysis in livestock, in which only phenotypic and pedigree information is available. Advantages and limitations of SEM compared to traditional approaches commonly used for the analysis of multiple traits, as well as some indication of future research in this area are presented in a concluding section.