Structural Model Analysis of Multiple Quantitative Traits

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Abstract
We introduce a method for the analysis of multilocus, multitrait genetic data that provides an intuitive and precise characterization of genetic architecture. We show that it is possible to infer the magnitude and direction of causal relationships among multiple correlated phenotypes and illustrate the technique using body composition and bone density data from mouse intercross populations. Using these techniques we are able to distinguish genetic loci that affect adiposity from those that affect overall body size and thus reveal a shortcoming of standardized measures such as body mass index that are widely used in obesity research. The identification of causal networks sheds light on the nature of genetic heterogeneity and pleiotropy in complex genetic systems. Disease states are often associated with multiple, correlated traits that may result from shared genetic and nongenetic factors. Genetic analysis of multiple traits can reveal a network of effects in which each trait is influenced by more than one genetic locus (heterogeneity) and different traits share one or more loci in common (pleiotropy). Physiological interactions independent of genetic factors may also contribute to the observed correlations. Structural equation modeling is proposed as a statistical method to characterize the architecture of multiple trait genetic systems. Application of structural equation modeling to body size, adiposity, and bone geometry traits illustrates how the effects of a genetic locus can be decomposed along direct and indirect paths that may be mediated through interactions with other traits. Using this technique the authors identify adiposity loci that act independently of loci affecting overall body size.