using the following criteria for marker selection: (i) evidence of moderation of drug response in at least two separate clinical trials; (ii) evidence of functional impact of variant on gene expression and/or endophenotypes of nicotine dependence in humans; and (iii) presence of gene within a relevant pharmacological pathway for the medication (bupropion) and nicotine dependence. This model incorporates four target genes based on evidence from single gene association studies examining variants in two genes associated with expression of dopamine D2 (DRD2) and D4 (DRD4) receptors, one for catechol-O-methyl transferase (COMT), and another for the dopamine transporter (SLC6A3). A systematic review and network analysis by Wang and Li suggested that the dopamine pathway loci with the strongest evidence of association with smoking cessation were DRD2 rs1800497, DRD4 VNTR, COMT rs4680 & SLC6A3 VNTR)(24). Two recent fMRI studies provide biologically plausible evidence of dopamine pathway genetic scores brain reward circuitry activation. Nikolova and colleagues reported that a similar, five locus (DRD2 −141C Del, DRD2 rs1800497, DRD4 VNTR, COMT rs4680 & SLC6A3 VNTR) dopamine pathway genetic risk score predicted 10.9% of the inter-individual variation in ventral striatum reactivity – a probable site of action for bupropion(25), which was greater than the contribution of
