Association of a Polyadenylation Polymorphism in the Serotonin Transporter and Panic Disorder

Background Genetic markers in the serotonin transporter are associated with panic disorder (PD). The associated polymorphisms do not include the serotonin transporter-linked polymorphic region and display no obvious functional attributes. A common polymorphism (rs3813034) occurs in one of the two reported polyadenylation signals for the serotonin transporter and is in linkage disequilibrium with the PD-associated markers. If functional, rs3813034 might be the risk factor that explains the association of the serotonin transporter and PD. Methods Quantitative polymerase chain reaction on human brain samples ( n = 65) and lymphoblast cultures ( n = 71) was used to test rs3813034 for effects on expression of the polyadenylation forms of the serotonin transporter. rs3813034 was also tested for association in a sample of PD cases ( n = 307) and a control sample ( n = 542) that has similar population structure. Results The balance of the two polyadenylation forms of the serotonin transporter is associated with rs3813034 in brain ( p < .001) and lymphoblasts ( p < .001). The balance of the polyadenylation forms is also associated with gender in brain only ( p < .05). Association testing of rs3813034 in PD identified a significant association ( p = .0068) with a relative risk of 1.56 and 1.81 for the heterozygous and homozygous variant genotypes, respectively. Conclusions rs3813034 is a functional polymorphism in the serotonin transporter that alters the balance of the two polyadenylation forms of the serotonin transporter. rs3813034 is a putative risk factor for PD and other behavioral disorders that involve dysregulation of serotonergic neurotransmission.