Genetic association studies of opioid use disorder have also implicated neurotransmission mechanisms in the glutamatergic pathway in addition to the classically identified dopamine and GABA pathways (Table 5). A recent GWAS reported a significant association with CNIH3, a gene whose product functions in the glutamtergic pathway and encodes for the production of cornichon family AMPA receptor auxiliary protein 3 (Nelson et al., 2016). This protein increases surface expression of AMPA ionotropic glutamate receptors and mediates channel conductance by slow deactivation and desensitation kinetics (Schwenk et al., 2009). Additionally, a recent study reported significant associations between SNPs in the genes KCNC1 and KCNG2 and a symptom count for opiate dependence (N =12,309). The product of these genes produce membrane proteins that mediate voltage-dependent potassium permeability and thus cellular excitability. Variants in the PITPNM3 locus were also reported to be significantly associated with opiate dependence. The product of this gene is a protein that is involved in phosphatidylinositol transport and is likely to be involved in calcium signalling and long-term potentiation, which is important for metaplasticity and learning (Sanna et al., 2002).
