We also used PRS to compare the three opioid-related phenotypes – dependence (with exposed controls – ODexposed – and with unexposed controls – ODunexposed) and exposure in non-dependent individuals (OEcontrols). Similarly to other addictive substances, illicit opioid users would be expected to have greater propensity to risk-taking behaviors, impulsivity, and stress responsivity than unexposed subjects38. Accordingly, we derived a PRS from the large-scale GWAS (N=466,571) conducted by the Social Science Genetic Association Consortium (SSGAC) on risk tolerance, which was defined as the tendency, preparedness, or willingness to take risks in general34. The PRS analysis was conducted on European-ancestry subjects only due to the well-known lack of large-scale GWAS in other ancestry groups39. The risk-tolerance PRS was positively associated with OD when contrasted with unexposed controls (ODunexposed: Neffective=4,728, PT=1, z=3.94, p=8.1×10−5, FDR q=0.003), whereas OD contrasted with exposed controls displayed only a trend (p<0.1; ODexposed: Neffective=3,038, PT=1, z=1.93, p=0.054, FDR q=0.13). OE (OEcontrol: Neffective=5,376, PT=0.05, z=3.57, p=3.6×10−5, FDR q=0.003) was also significant for the risk-tolerance PRS.
