analyses captured the role of subthreshold results to reveal two potentially functional pathways, calcium signaling and synaptic long term potentiation. Neurotransmitter signaling plays a key role in drug dependence [3,15]; CAMK2B (calcium/calmodulin dependent protein kinase II beta) was shown to be a hub molecule in pathways relevant to drug addiction [16], whereas long term potentiation could modulate heroin relapse through the glutamate receptor NR2B (NMDA2b-containing receptor) [17]. The groundbreaking study by Nelson et al [14] utilized a novel and highly valid design, the comparison of exposed and non-exposed controls with affected individuals. Most genetic studies in addiction tend to use unexposed controls which are useful for assessing dependence on drugs but tend to lead to reduced power when analyzing intermediate or later stages of addiction. Comparison of opioid-dependent subjects with opioid misusers, namely those individuals who had not progressed to dependence, revealed a protective role of variants in the gene CNIH3 (cormichon family AMPA receptor auxiliary protein 3). Identification of protective variants is useful as these could serve as biomarkers to prevent transition from opioid use to dependence, and thus help translational work.
