Human serotonin transporter gene (SLC6A4) variants: their contributions to understanding pharmacogenomic and other functional G x G and G x E differences in health and disease

Recent major findings from studies of SLC6A4 and its corresponding protein, the serotonin (5-HT) transporter (SERT) in humans, rodents and non-human primates indicate that combinations of SLC6A4 non-coding 5', 3' UTRs and intronic regions plus coding variants acting together can change 5HT transport as much as 40-fold in vitro. In vivo, SLC6A4 variants in humans and other species lead to marked physiological changes, despite mitigating neurodevelopmental adaptations in 5-HT receptors plus compensatory alterations in 5-HT synthesis and metabolism. Polymorphisms in SLC6A4 are associated with differences in emotional, endocrine, and personality characteristics as well as many diseases. This gene, in combinations with gene x gene (G x G) and gene x environment (G x E) interactions nonetheless remains incompletely understood, with some association findings remaining controversial. Considering its primary importance in the regulation and function of the entire serotonergic system (as evidenced by the consequences of SERT-mediated reuptake inhibition by SRIs like fluoxetine in humans and of genetically engineered changes in mice and rats), it seems likely that SLC6A4 and SERT will remain areas of high interest in our field's attempts to better understand and treat 5-HT-related disorders.