The finding that SUDs share a large proportion of variance with externalizing phenotypes is consistent with previous phenotypic SEM and twin literature. Many structural models of psychopathology include SUDs in the externalizing dimension,22,23 and twin studies have found that genetic and environmental influences on SUDs largely operate through a broad externalizing factor.8,46 Many structural models, however, place SUDs within specific subdimensions of externalizing, thus acknowledging variance that is unique to SUDs and not shared with all other forms of externalizing. For example, in the externalizing spectrum model,10 substance use related traits are a subdimension of general externalizing and, in the HiTOP model,36 SUDs are part of an externalizing subdimension representing disinhibited forms of externalizing, which are distinct from antagonistic forms. The number of well-powered GWAS of externalizing phenotypes may limit our ability to detect dimensionality in the current analyses and, as more GWAS of relevant traits become available, a more complex, hierarchical genetic architecture may be uncovered.
