Biologically relevant combinations of functional variants within gene networks are likely to have additive effects on risk for addiction. Needless to say, even with high frequency variants, very large sample sizes are required to detect differences between carriers of different genotype combinations. Recent examples come from SLC6A4, the gene encoding the serotonin transporter, and HTR3A / HTR3B, the genes that encode the 5-HT3 receptor which mediates fast excitatory 5-HT transmission. We recently demonstrated additive effects between a functional SLC6A4 promoter polymorphism 5-HTTLPR and a common functional HTR3B coding polymorphism on risk for alcohol and drug dependence [55]. The explanation for these additive effects on addiction might be that the resulting increased synaptic 5-HT coupled with increased 5-HT3 receptor responsiveness might lead to enhanced DA transmission in the reward pathway. Likewise, another group was able to identify genotype combinations across SLC6A4, HTR3A and HTR3B that increased risk for AUD [56] and predicted the response of alcoholics to the 5-HT3 antagonist ondansetron [57]. Although exploratory at this stage and requiring very large sample sizes for validation, these kinds of studies could result
