Human serotonin transporter gene (SLC6A4) variants: their contributions to understanding pharmacogenomic and other functional G × G and G × 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 × gene (G × G) and gene × environment (G × 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.

► Recent findings from studies of SLC6A4 and SERT indicate that combinations of variants can affect 5-HT transport and transporter expression up to 40-fold in vitro. ► Multiple functional SLC6A4 variants include 5′ region (5HTTLPR, rs25531 and rs25532), 3′-UTR region variants plus intronic (Stin2) and coding variants. ► Most of these different SLC6A4 variants have been associated with neuropsychiatric and other medical disorders, from autism and OCD to cardiovascular diseases. ► Some of these associations such as those linking stress, amygdala functions and affective disorders appear to depend upon gene–environment (G × E) and gene–gene (G × G) interactions. ► Some of the discoveries regarding the functional consequences of SLC6A4 variants have pharmacogenomic relevance for antidepressant SRIs and other drug therapeutics.