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.


RESULTS
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.


CONCLUSIONS
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.
Kraft
Jeffrey B
JB
Department of Psychiatry and Center for Human Genetics, University of California-San Francisco, 401 Parnassus Avenue, San Francisco, CA 94143-0984, USA.
Slager
Susan L
SL
McGrath
Patrick J
PJ
Hamilton
Steven P
SP
D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D017421:Sequence Analysis / Q000379:methods; D050486:Serotonin Plasma Membrane Transport Proteins
D000928:Antidepressive Agents; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins