Although several putative single-variant, gene-based, and PRS associations were identified based on the different OD and OE phenotypes, the sample size of the current investigation is still small, given the polygenic architecture of psychiatric disorders57. Novel studies specifically targeting SUDs and assessing opioid-related behaviors will be necessary to recruit cohorts informative for OD and OE GWAS. Another important limitation is the phenotypic heterogeneity within the opioid exposure sample, which included individual exposed to opioids via licit use (i.e., medical prescriptions) and illicit use. There may be important differences between these two subgroups (e.g., risk-taking may be more strongly associated with illicit exposure). However, several of the cohorts investigated lacked this information, and, due to the limited sample size, we were not able to make this comparison. In addition, this may have resulted in heterogeneity in the OU controls (i.e., those who reported not using opioids illicitly were unassessed for medical exposure). Future large opioid-informative datasets will be needed to determine whether illicit and licit opioid exposure have distinct effects on the molecular basis of opioid dependence. Finally, while the phenome-wide
