Functional gene variation in the human norepinephrine transporter - Association with attention deficit hyperactivity disorder

The norepinephrine (NE) transporter (NET) is responsible for the re-uptake of NE into presynaptic nerve terminals, thus critically regulating noradrenergic signaling and homeostasis. Since NE signaling contributes to diverse brain functions, we hypothesize that promoter variation within the human NET gene (solute carrier family 6, member 2; SLC6A2) may impact risk for NE-related disorders, including depression, attention deficit hyperactive disorder (ADHD), and autonomic dysfunction. In support of this, we recently found a functional polymorphism at -3081 position upstream of the transcription initiation site. This polymorphism displayed differential promoter function, which we showed could arise from recruitment of a transcriptional repressor. Further analyses identified Slug and Scratch as candidates involved in repression of SLC6A2 transcription generated by the -3081(T) allele. Moreover, we observed a significant association of the -3081(T) variant with ADHD. Altered transcription of SLC6A2 may therefore represent a novel risk factor for the development of ADHD.