Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder

Battersby, S.; Ogilvie, Alan D.; Smith, Colin; Blackwood, Douglas; Muir, Walter; Quinn, JP; Fink, George; Goodwin, G M; Harmar, Anthony J.

doi:10.1097/00041444-199624000-00001

Cited by 118 publications

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“…In total, 17 population-based studies 9,14,33,34,38,46,50,51,56,60,61,66,[68][69][70] and six family-based studies 12,32,42,53,63,74 were about 5-HTTLPR. A total of 16 population-based studies 27,33,35,38,41,47,[49][50][51]54,56,58,60,61,70,75 and four family-based studies 12,52,57,63 were about the intron 2 VNTR. Among the population-based studies, some used matched controls according to the ethnicity 41,47,50,60,66,69 and others explicitly verified the ethnic homogeneity of the sample through the ancestry history.…”

Section: Resultsmentioning

confidence: 99%

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Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

et al. 2005

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The serotonin transporter (5-HTT) is a candidate gene for bipolar disorder (BPD). It has been investigated for association with the illness in a series of studies, but overall results have been inconsistent and its role in the disorder remains controversial. Systematic reviews using metaanalytical techniques are a useful method for objectively and reproducibly assessing individual studies and generating combined results. We performed two meta-analyses of published studies-both population-based and family-based studies-investigating the association between BPD and the 5-HTT gene-linked polymorphic region (5-HTTLPR) and the intron 2 variable numbers of tandem repeats (VNTR) polymorphisms. The literature was searched using Medline and Embase to identify studies for inclusion. We statistically joined population-based and family-based studies into a single meta-analysis. For both polymorphisms, our review revealed significant pooled odds ratios (ORs): 1.12 (95% CI 1.03-1.21) for the 5-HTTLPR and 1.12 (95% CI 1.02-1.22) for the intron 2 VNTR. Meta-regression showed that neither the study type (population-based vs family-based; P ¼ 0.41 for the 5-HTTLPR and P ¼ 0.91 for the intron 2 VNTR) nor the sample ethnicity (Caucasian vs non-Caucasian; P ¼ 0.35 for the 5-HTTLPR and P ¼ 0.66 for the intron 2 VNTR) significantly contributed to the heterogeneity of the meta-analyses. The observed ORs could be regarded simply as a very small but detectable effect of the 5-HTT, which has an additive effect when combined with other susceptibility loci. Alternative hypotheses on this finding were also discussed: a stronger effect of the haplotypes involving the two polymorphisms or other SNP markers; a more direct effect of these polymorphisms on specific phenotypes of BPD; and the presence of gene-environment interaction as a mediator of the genetic effects of 5-HTT. Keywords: bipolar disorder; serotonin transporter; polymorphisms; genetics; association study; meta-analysis Bipolar disorder (BPD), also known as manic-depressive illness, is a frequent and severe psychiatric disorder with the lifetime prevalence between 1 and 2% in the general population, being equally distributed across sexes. 1 The etiology is unknown although the presence of a complex dysfunction at multiple levels such as neurotransmitter system, prefrontallimbic-subcortical circuit and neuroendocrinological system has been suggested. 2 Family studies have indicated a marked increase in lifetime risk of the illness in first-degree relatives of the proband, varying between five and 10 times that of the general population. 3 Twin studies have shown an increased risk in monozygotic co-twins compared with dizygotic co-twins of a proband with BPD. The risk in monozygotic co-twins has been estimated at 45-75 times that of the general population. 3,4 Adoption studies have also shown that the risk of BPD is greater in biological relatives than in adoptive relatives of the probands. 5 Most of the segregation studies have shown that the inheritance of BPD cannot be explained b...

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Section: Resultsmentioning

confidence: 99%

“…51 The remaining studies mentioned that the sample was ethnically homogeneous. 9,14,34,35,49,54,58,61,68,70,75 5-HTTLPR meta-analysis In total, 17 population-based studies comprised 1712 cases (ie 3424 alleles) and 2583 controls, whereas six family-based studies comprised 587 trios. Summaries are shown in the Tables 1 and 2.…”

Section: Resultsmentioning

confidence: 99%

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

et al. 2005

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“…Among these, 11 investigated the promoter 44 bp ins/del polymorphism 14,20,[33][34][35][36][37][38][39][40][41] and 10 studies investigated the VNTR polymorphism. [42][43][44][45] The studies by Kunugi et al 46 and by Ogilvie et al 47 were excluded since they were not independent from the studies by Kunugi et al 36 and Battersby et al, 42 both of which were included.…”

Section: Major Depression and 5-httmentioning

confidence: 99%

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders

2003

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The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR ¼ 1.14, CI: 1.03-1.26, P ¼ 0.015 for the promoter locus (N ¼ 3467) and Mantel-Haenszel Weighted odds ratio OR ¼ 1.18, CI: 1.05-1.32, P ¼ 0.004 for the VNTR locus (N ¼ 3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between BD and 5-HTT.

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“…[10][11][12] Indeed, an elevated propensity toward abnormal emotional behavior is noted in adult animals chronically treated with antidepressants during early development, [12][13][14] or in individuals genetically expressing low levels of SERT. [15][16][17][18] Therefore, although SERT-knockout mice represent a useful model for investigating disorders involving genetic alterations in SERT during early life, 11,19 they are less appropriate for studying the partial SERT downregulation observed following chronic use of SSRIs. Moreover, these mice fail to establish the functional relevance of downregulating SERT during adulthood.…”

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siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain

et al. 2005

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Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressant drugs that increase the extracellular levels of serotonin by blocking the reuptake activity of the serotonin transporter (SERT). Although SSRIs elevate brain serotonergic neurotransmission acutely, their full therapeutic effects involve neurochemical adaptations that emerge following chronic drug administration. The adaptive downregulation of SERT has recently been implicated in the therapeutic response of SSRIs. Interestingly, studies using SERT-knockout mice reveal somewhat paradoxical depression-related effects, probably specific to the downregulation of SERT during early development. However, the behavioral significance of SSRI-mediated downregulation of SERT during adulthood is still unknown. We investigated whether somatic gene manipulation, triggered by infusing short interfering RNA (siRNA) into the ventricular system, would enable the downregulation of SERT in the adult mouse brain. Infusing the SERT-targeting siRNA, for 2 weeks, significantly reduced the mRNA levels of SERT in raphe nuclei. Further, a significant, specific and widespread downregulation of SERT-binding sites was achieved in the brain. In contrast, 2-week infusion of the SSRI, citalopram, produced a widespread downregulation of SERT-binding sites, independent of any alterations at the mRNA level. Irrespective of their mechanisms for downregulating SERT in the brain, infusions of SERT-siRNA or citalopram elicited a similar antidepressant-related behavioral response in the forced swim test. These results signify a role for the downregulation of SERT in mediating the antidepressant action of SSRIs in adults. Further, these data demonstrate that siRNAinduced widespread knockdown of gene expression serves as a powerful tool for assessing the function of endogenous genes in the adult brain. The serotonin transporter (SERT) controls the temporal and spatial activity of extracellular serotonin by facilitating a rapid and high-affinity reuptake of this neurotransmitter into presynpatic terminals. 1 SERT is also a primary molecular target for the most widely prescribed antidepressant drugs, the selective serotonin reuptake inhibitors (SSRIs). 2 SSRIs readily inhibit SERT activity and elevate the serotonergic tone in the brain. However, full therapeutic benefits ensue only after chronic use of SSRIs, requiring the manifestation of long-term adaptations, secondary to the blockade of serotonin reuptake. 3,4 Emerging studies reveal downregulation of SERT as an adaptive consequence of sustained and high occupancy by chronically administered SSRIs. 5-8 The downregulation of SERT favorably potentiates the SSRI-mediated increase in the brain serotonergic neurotransmission. [6][7] Further, the lag time required by SSRIs to produce a substantial downregulation of SERT correlates well with the time needed for eliciting a full therapeutic response. Therefore, downregulation of SERT has been implicated in the antidepressant action of SSRIs. 7 Recently, SERT-deficient mice were used ...

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Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder

Cited by 118 publications

References 0 publications

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders

siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain

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