Combining a factor analytic approach with an enrichment analysis of an independently developed gene set is a novel method for examining the extent to which genes associated with alcohol outcomes also associate with externalizing more generally. This approach provides advantages both in terms of strong phenotypic measurement and by providing a degree of genetic specificity not afforded by some genome-wide approaches by relying on prior evidence. In addition, by using a bi-factor model with residual domain-specific factors (Latendresse et al., 2015), we can test if enrichment effects are present for specific behaviors over and above the common variance shared across domains. Our hypothesis is that the enrichment will primarily be evident for a general externalizing factor, rather than for residual variance specific to certain behaviors, given the strong genetic signal for common variance identified in twin studies (Krueger et al., 2002).
