unexposed controls). A PRS based on a GWAS of neuroticism43 was positively associated with OD (OD cases versus unexposed controls and OD cases versus exposed controls) but not with opioid exposure (exposed versus unexposed controls). These analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls (exposed versus unexposed) in opioid studies: only subjects who are exposed to a substance have the opportunity to become dependent; thus unexposed controls can also be considered “diagnosis-unknown”. The importance of this distinction depends largely on the risk of eventually becoming dependent upon esposure.
