This SNP rs16969968 is a high priority variant for potential functional effect: the change in amino acid 398 from aspartic acid (encoded by the G allele) to asparagine (encoded by A, the minor allele) results in a valence change, as noted in [6]. We also have recent data that this D398N amino acid change directly results in a change in function for the receptor [11]. Most important for the present study, rs16969968 has now been shown to be associated with cocaine dependence in two independent European-American samples from the FSCD and from the Collaborative Study on the Genetics of Alcoholism [9]. Interestingly, the risk allele for nicotine dependence appears to be protective for cocaine dependence, suggesting that the involvement of nicotinic receptors (nAChRs) in addiction is complex. The nAChRs are well known to be involved in both excitatory and inhibitory neurons impacting dopamine transmission, and this dual involvement provides biological plausibility for a bidirectional effect of the same genetic variant. Our goal in this report is now to examine the SNPs correlated with rs16969968 across the European American and African American samples in the FSCD to narrow and define the association signal.
