Another key potential contributor to the lack of consistency in findings from prior GWAS is that different study designs were used. The most relevant design variation is related to the assessment of opioid exposure in controls. Two different control definitions have been considered: i) individuals exposed to opioids (OE) medically or illegally who did not develop OD; or ii) individuals without an OD diagnosis who were not assessed for opioid exposure. Although including individuals not exposed to opioids in the control group increases the overall sample size, it also potentially adds noise by including individuals who would have been likely to become OD if exposed, given the highly addictive nature of opioid drugs. Furthermore, exposure to opioids is a behavioral trait per se, and likely to be associated with its own specific genetic architecture, which may be different between licit 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
