We investigated the genetic architecture of opioid-related traits in informative cohorts. Our comparison of opioid dependence (OD) compared with unexposed (ODunexposed) and exposed (ODexposed) controls, as well as of opioid exposure among controls (OEcontrols) provides new insights into opioid addiction. We identified GWS loci and genes for ODunexposed and OEcontrols, and found these variants to be associated with health relevant traits in the UK Biobank. Most critically, our PRS analyses highlighted distinctions between exposed and unexposed controls, as well as the progression from exposure to dependence. Use and dependence are behaviors with different relationships to other genetically influenced traits, as has been shown for alcohol use vs. alcohol dependence13, 14. To our knowledge, no previous study investigated the specific genetic differences between OD and OE; our current findings provide the first insights based on genome-wide data into the molecular mechanisms by which OE and OD differ. The lack of sufficiently large numbers of OD cases and OE controls is a fundamental barrier to facilitating our understanding of the biological underpinnings of this serious public health epidemic, as it limited the power of what we would regard as the most informative comparison.
