Sequence Analysis of the Serotonin Transporter and Associations with Antidepressant Response

• Published in: Biological psychiatry (1969) Vol. 58; no. 5; pp. 374 - 381
• Main Authors: Kraft, Jeffrey B., Slager, Susan L., McGrath, Patrick J., Hamilton, Steven P.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2005; Elsevier Science
• Subjects: activator protein 2; Adult; Adult and adolescent clinical studies; antidepressant; Antidepressive Agents - therapeutic use; association; Biological and medical sciences; Chromatography, High Pressure Liquid - methods; Depression; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - genetics; Electrophoretic Mobility Shift Assay - methods; Exons; Female; Genotype; Humans; Linkage Disequilibrium - physiology; Male; Medical sciences; Membrane Glycoproteins - drug effects; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Membrane Transport Proteins - drug effects; Membrane Transport Proteins - genetics; Membrane Transport Proteins - physiology; Middle Aged; Molecular Sequence Data; Mood disorders; Nerve Tissue Proteins - drug effects; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neuropharmacology; pharmacogenetics; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - biosynthesis; sequence; Sequence Analysis - methods; Serotonin Plasma Membrane Transport Proteins; Serotonin transporter; single nucleotide polymorphism; activator protein 2; sequence; Serotonin transporter; single nucleotide polymorphism; antidepressant; association; pharmacogenetics; Human; Nucleotide sequence; Serotonin; Psychotropic; Biological transport; Protein; Promoter; Chemotherapy; Treatment; Neurotransmitter; Antidepressant agent; Polymorphism
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2005.04.048

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. 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.