Sequence Analysis of the Serotonin Transporter and Associations with Antidepressant Response

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

“…Studies by Kraft et al 28 and Minov et al 30 were excluded because they included patients treated by a mixture of antidepressants. The paper by Lee et al 29 was not included because it did not use HAM-D or MADRS but Clinical Global Impressions of Improvement (CGI) score.…”

“…39,40 A wider list of polymorphism should be investigated to achieve a better resolution given that other control regions may be present for the 5-HTT expression, not to mention possible enhancers or silencers located in other regions far from the gene locus. In fact, Hamilton et al 28,41 reported a significant association of a functional SNP (rs25531) 42,43 located just upstream of the 5-HTTLPR with antidepressant response to fluoxetine treatment and in linkage disequilibrium (LD) with 5-HTTLPR. In the presence of the g allele of this SNP, the l allele of 5-HTTLPR seems to be associated with nonresponse, while this is the case for the s allele in presence of the a allele of the SNP.…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…69,104 An adenosine/guanine (A/G) single-nucleotide polymorphism (SNP) located within the repeats of 5-HTTLPR seems to be relatively common even in Caucasian populations, with a minor (G) allele frequency (MAF) of 10%; it has been described as rs25531 SNP associated with either short or long 5-HTTLPR alleles 105 or as a L A /L G modifier of the long allele. 106 Wendland and colleagues 107 have demonstrated that the disagreement was caused by two alternative demarcations of the 5-HTTLPR insertion sequence and that the G/A rs25531 SNP can be associated with either l or s allele.…”

Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531

“…Rare gain-of-function coding mutations such as Ile425Val and Gly56Ala have recently been discovered, 1,2 while common noncoding polymorphisms that impact transcription include an intron 2 VNTR and the 5-HTT-linked polymorphic region (5-HTTLPR). 3,4 The latter polymorphism is commonly subdivided into S (short, lesser expressing) and L (long, greater expressing) alleles based on the presence of a 43 bp indel (initially described as 44 bp) 3,5,6 and has been extensively analyzed in over 300 behavioral, psychiatric, pharmacogenetic and other medical genetics papers over the past 10 years. 7,8 Recent reports have raised the possibility that the established subdivision of 5-HTTLPR into S and L alleles requires reconsideration.…”

“…Another report, in turn, presented data on a potentially functional SNP (rs25531) located immediately upstream of the indel in an AP-2 binding region. 6 While at first sight these two SNPs might appear to be two physically distinct loci, a detailed alignment presented in Figure 1a shows that, in fact, both refer to the same nucleotide located at the 10th position after the e element denoted by Nakamura et al 5 This alignment also demonstrates that the boundaries of the 43 bp indel can be set in different ways; Hu et al report the SNP as being located at the sixth cytosine of the insertion and use the boundaries as originally described, 3,10 while Kraft et al 6 locate the insertion further downstream and thus the same SNP then lies upstream of the indel (Figure 1a).…”