Sequence analysis of the serotonin transporter and associations with antidepressant response

Background: The serotonin transporter is the molecular target of many antidepressants, and the gene (SLC6A4) encoding this protein has been associated with response to selective serotonin reuptake inhibitors (SSRIs). We sought to test further the hypothesis that SLC6A4 is associated with SSRI response by resequencing this gene in subjects with major depression. Methods: The sequence of all exons, parts of all introns, and the promoter region containing a polymorphic repeat polymorphism (HTTLPR) previously associated with SSRI response was determined for 96 subjects, and variants were tested for association to treatment response with fluoxetine. We screened a total of 712 kilobases of sequence and found 27 SLC6A4 variants, 21 of which were previously undescribed. Seventeen were seen on one chromosome each, including three of the five exonic variants. One polymorphism (rs25531), just upstream of the HTTLPR, showed evidence of an association with treatment response, and biochemical experiments showed this polymorphism altered binding of nuclear extracts to a consensus sequence for the activator protein 2 transcription factor, which is believed to be a critical factor in regulating neural gene expression in mammals. These results support an association between response to SSRIs and deoxyribonucleic acid variation at the serotonin transporter locus. We have also identified a potentially important functional variant that contributes to this association and a possible biologic mechanism that could mediate its effect.