and illicit exposure. Opioid use is rarer than the use of many other substances and it is often observed in individuals affected by severe mental and physical illnesses11, 12. Comparisons of OD cases with predominantly unexposed controls is likely to confound genetic risk for exposure to opioids with genetic factors specific to the transition to OD. Indeed, at least one prior smaller GWAS7 found that comparisons of OD cases to controls with significant exposure and from similar neighborhoods resulted in a GWS finding while comparisons with general population controls did not identify any GWS variants.
