Though prior genetic studies of comorbidity have been necessarily limited in scope (e.g., to common disorders among related individuals), the development of polygenic risk scores (PRS; Purcell et al., 2009)—continuous indices of individual risk based on summary statistics from a genomewide association study (GWAS)—has allowed for examination of shared cross-trait genetic influence in unrelated and non-patient samples (e.g., Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013; Krapohl et al., 2015). The aim of the current study was to examine general and specific genetic associations between psychiatric disorders and substance involvement using PRS derived from the PGC cross-disorder meta-analysis in a sample of 2573 non-Hispanic European–American participants ascertained for substance dependence in the Study of Addiction: Genetics and Environment (SAGE; Bierut et al., 2010). We first tested associations between cross-disorder polygenic risk (CROSS) and a general substance involvement factor (GENSUB). GENSUB was used due to evidence from twin studies that a large proportion of genetic liability is shared across substances (Kendler et al., 2003; Agrawal et al., 2012) and the use of a similar factor score in a prior GWAS (Wetherill
