Analysis of the residual SUD genetic effects revealed several interesting insights into their neurobiology. First, many genes identified for the residuals were involved in substance specific pharmacokinetic and pharmacodynamic processes (e.g., ADH1B, CHRNA5), potentially indicating that genetic liability to addiction is made up of risk general to externalizing and risk related to an individuals’ biological sensitivity to each specific substance. Second, genetic correlation analyses suggested that most cross substance genetic associations (e.g., correlations between CUD and alcohol phenotypes) are explained by shared externalizing variance. In addition, most SUDs retained significant associations with other forms of psychopathology (e.g., internalizing and thought disorders), highlighting the complex interface between SUDs and a broad range of psychopathology. Finally, the residual PGS showed substance specific prediction such that the residual PGS for a specific SUD best predicted that SUD in an independent sample. This highlights the potential translational utility of broad and specific PGS whereby a broader metric of risk captures an individual’s general liability to addiction whereas specific metrics can provide insight into risk for problems with specific substances. Relative to the previous externalizing
