Despite some encouraging initial findings (Carter, 2006), there is not yet compelling evidence of the involvement of genes encoding proteins involved in glutamate signaling in addiction vulnerability. In this study, we hypothesized that NMDAR-related RVs (minor allele frequency (MAF) ≤ 1%) play important roles in SD. To test the hypothesis, we sequenced the coding exons and their flanking intronic regions of 17 genes related to NMDARs and NMDAR function for 760 individuals with co-occurring diagnoses of alcohol dependence (AD), cocaine dependence (CD) and opioid dependence (OD), and 760 healthy controls. We chose subjects who were dependent on all three substances for the purpose of increasing statistical power, because sampling individuals with extreme phenotypes can enrich the presence of risk rare variants (Barnett et al., 2013). We followed up 11 RVs in an independent sample of 6751 subjects with a high percentage of SD (where contributions to the individual SD traits could also be disambiguated). We observed that in African Americans (AAs), RVs in DISC1 and GRIN2B affect the risk of OD, with stronger evidence in DISC1 than GRIN2B.
