Analyses of candidate gene data in the current report’s discovery sample, the Comorbidity and Trauma Study (CATS), showed that association findings vary substantially depending on the comparison group’s substance exposure status.6,7 The current investigation builds on this observation and draws from genetic studies of licit drugs13–19 that have yielded well-replicated findings by comparing non-dependent, drug-exposed to substance dependent individuals. Unfortunately, no large samples of non-dependent opioid misusers have been collected. Our discovery6,7,20 and confirmation samples19,21–24 contain only modest numbers of non-dependent opioid misusers, but are currently the largest such samples with genome-wide association study (GWAS) data. We hypothesize that genetic polymorphisms in opioid misusers influence progression to the population’s opioid dependence endpoint (ODE). Our analyses of GWAS data observed the strongest association for cornichon family AMPA receptor auxiliary protein 3 (CNIH3) polymorphisms, findings which map nicely onto literature25–29 supporting AMPA glutamate system involvement in the pathophysiology of opioid dependence.
