title: SLC6A4 variation and citalopram response.
abstract: The influence of genetic variations in SLC6A4 (serotonin transporter gene) on citalopram treatment of depression using the Sequenced Treatment to Relieve Depression (STAR*D) sample was assessed. Of primary interest were three previously studied polymorphisms: 1) the VNTR variation of the second intron, 2) the indel promoter polymorphism (5HTTLPR or SERT), and 3) a single nucleotide polymorphism (SNP) rs25531. Additionally, SLC6A4 was resequenced to identify new SNPs for exploratory analyses. DNA from 1914 subjects in the STAR*D study were genotyped for the intron 2 VNTR region, the indel promoter polymorphism, and rs25531. Associations of these variants with remission of depressive symptoms were evaluated following citalopram treatment. In white non-Hispanic subjects, variations in the intron 2 VNTR (point-wise P = 0.041) and the indel promoter polymorphism (point-wise P = 0.039) were associated with remission following treatment with citalopram. The haplotype composed of the three candidate loci was also associated with remission, with a global p-value of 0.040 and a maximum statistic simulation p-value of 0.0031 for the S-a-12 haplotype, under a dominant model. One SNP identified through re-sequencing the SLC6A4 gene, Intron7-83-TC, showed point-wise evidence of association, which did not remain significant after correction for the number of SNPs evaluated in this exploratory analysis. No associations between these SLC6A4 variations and remission were found in the white Hispanic or black subjects. These findings suggest that multiple variations in the SLC6A4 gene are associated with remission in white non-Hispanic depressed adults treated with citalopram. The mechanism of action of these variants remains to be determined.
authors.affiliation: Mayo Clinic, Department of Psychiatry and Psychology, Rochester, Minnesota, USA. mrazek.david@mayo.edu
authors.forename: D A
authors.initials: DA
authors.lastname: Mrazek
authors.forename: A J
authors.initials: AJ
authors.lastname: Rush
authors.forename: J M
authors.initials: JM
authors.lastname: Biernacka
authors.forename: D J
authors.initials: DJ
authors.lastname: O'Kane
authors.forename: J M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: E D
authors.initials: ED
authors.lastname: Wieben
authors.forename: D J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: M S
authors.initials: MS
authors.lastname: Drews
authors.forename: V L
authors.initials: VL
authors.lastname: Courson
authors.forename: K A
authors.initials: KA
authors.lastname: Snyder
authors.forename: J L
authors.initials: JL
authors.lastname: Black
authors.forename: R M
authors.initials: RM
authors.lastname: Weinshilboum
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000483:Alleles; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D015283:Citalopram / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012074:Remission Induction; D017422:Sequence Analysis, DNA; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
chemical_list: D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human