The serotonin transporter intronic VNTR enhancer correlated with a predisposition to affective disorders has distinct regulatory elements within the domain based on the primary DNA sequence of the repeat unit

Lovejoy, Elizabeth A.; Scott, A C; Fiskerstrand, C. E.; Bubb, Vivien J.; Quinn, John P.

doi:10.1046/j.1460-9568.2003.02446.x

Cited by 113 publications

(75 citation statements)

References 18 publications

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“…Particular emphasis has been placed on functional variants in the serotonin transporter gene (SERT, 5-HTT, SLC6A4), given an etiopathological hypothesis based on the effectiveness of serotonin reuptake inhibitors in the treatment of OCD. Studies have investigated common non-coding variants affecting transcriptional efficiency, such as the 43 bp promoter indel referred to as 5-HTTLPR and STin2, a variable number of tandem repeats polymorphism in intron 2 (Heils et al, 1995;Hranilovic et al, 2004;Hu et al, 2006;Lesch et al, 1995;Lovejoy et al, 2003;MacKenzie and Quinn, 1999). Rare coding mutations such as the gain-of-function I425V have also been reported as segregating in families with OCD probands (Ozaki et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Wendland

Kruse

Cromer

et al. 2007

Neuropsychopharmacol

101

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Both serotonin transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) genes have shown positive associations with obsessive-compulsive disorder (OCD) and some other psychiatric disorders, but these results have not been consistently replicated. To explore the hypothesis that this variability might result from the effects of differing combinations of overlooked variants within SLC6A4 together with small OCD and control sample sizes, we studied three common functional polymorphisms (5-HTTLPR, STin2, and the newly discovered SNP, rs25531) in the largest sample size of OCD patients (N ¼ 347) and controls (N ¼ 749) ever investigated. During methods development, we found evidence for potential SLC6A4 genotyping problems with earlier methodology, a third possible contributor to variability in earlier studies. A fourth possible explanation might be SLC6A4 Â BDNF interactions, which prompted us to investigate combined genotypes of BDNF V66M with the three SLC6A4 loci. Except for a nominal association with rs25531 alone, which did not survive correction for multiple comparisons, we found no evidence for any of these other variants being associated alone or together with OCD, and we therefore also examined clinical OCD subtypes within the sample to evaluate clinical heterogeneity. Subgroups based on the age of OCD onset, gender, familiality, factor analysis-derived symptom dimensions, or comorbidity with other psychiatric disorders failed to identify SLC6A4-or BDNF-associated phenotypes, with one exception of overall number of comorbid anxiety disorders being significantly associated with 5-HTTLPR/rs25531. We conclude that despite their attractiveness as candidate genes in OCD, our data provide no support for association in this large OCD patient sample and point toward the need to examine other genes as candidates for risk determinants in OCD.

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Section: Introductionmentioning

confidence: 99%

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Wendland

Kruse

Cromer

et al. 2007

Neuropsychopharmacol

101

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“…1). We have demonstrated that the different repeat number within the VNTR supports differential expression in vitro (Fiskerstrand et al, 1999;Lovejoy et al, 2003) and both differential and tissuespecific expression in vivo (MacKenzie and Quinn, 1999) in a transgenic model. It has also been demonstrated that the VNTR genotype correlates with the number of platelet 5-HTT transporters in patients with affective disorders (Mellerup et al, 2001).…”

Section: Introductionmentioning

confidence: 78%

“…We have previously demonstrated the ability of the VNTR domains to support reporter gene expression in vivo and in vitro (Fiskerstrand et al, 1999;MacKenzie and Quinn, 1999;Lovejoy et al, 2003). To further investigate the ability of YB-1 to regulate the VNTR domains, we used luciferase reporter gene constructs containing VNTR domains inserted upstream of the SV40 promoter termed pStin2.9Luc, pStin2.10Luc, and pStin2.12 Luc.…”

Section: Yb-1 Can Specifically and Differentially Activate The Distinmentioning

confidence: 99%

YB-1 and CTCF Differentially Regulate the 5-HTT Polymorphic Intron 2 Enhancer Which Predisposes to a Variety of Neurological Disorders

Klenova¹,

Scott²,

Roberts³

et al. 2004

J. Neurosci.

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“…Functionally, the alleles of STin2 VNTR (STin2.10 and STin2.12) can act as transcriptional regulatory elements, with STin2.12 having a superior enhancer-like property within the developing rostral hindbrain, which may lead to aberrant serotonergic neuron development. 32,33 In spite of the evidence for functional effects of alleles at STin2 VNTR, it is not possible to determine whether this VNTR is causally associated with increased risk of schizophrenia. It has been suggested that individual polymorphisms have a weak influence when compared with the combined effect of 5-HTTLPR and STin2 VNTR polymorphisms on SLC6A4 expression.…”

Section: Discussionmentioning

confidence: 99%

Evidence of association of serotonin transporter gene polymorphisms with schizophrenia in a South Indian population

et al. 2009

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Serotonin (5-hydroxytryptamine (5-HT)) transporter (SLC6A4) is known to influence mood, emotion, cognition and efficacy of antidepressants, particularly that of selective serotonin reuptake inhibitors. Atypical antipsychotics exert their effects partially through serotinergic systems, and hence, variation in 5-HT uptake may affect antipsychotic action mediated through the serotinergic system. Therefore, investigating the role of SLC6A4 as a risk factor for developing schizophrenia and treatment response had been a point of concern for many investigators, but with variable outcome. In this study, we examined the genetic roles of five polymorphisms of SLC6A4, including those of the widely studied 44 base pair variable number of tandem repeat (VNTR) in the promoter region of SLC6A4 (the serotonin transporter gene-linked polymorphic region: 5HTTLPR) and a VNTR polymorphism (STin2) in the second intron, in schizophrenia and its influence on the severity of symptoms in a South Indian population from Kerala, comprising 586 individuals. We detected significant allelic and genotypic associations with rs2066713 (both allelic and genotypic P-value o0.001), 5HTTLPR (allelic P-value¼0.008 and genotypic P-value¼0.03) and STin2 polymorphisms (allelic P-value¼0.001 and genotypic P-value¼0.002). A haplotype linking these three risk alleles, 5HTTLPR/ S-rs2066713/C-STin2/12-repeat (P-value¼0.0059), was also significantly associated with disease in our population. Patients with STin2 12-repeat homozygotes showed a greater severity of blunted effect symptom. These results suggest a strong role of SLC6A4 in schizophrenia, possibly with a specific behavioral endophenotype in a South Indian population. Keywords: case-control; SLC6A4; schizophrenia; South India; symptom profile INTRODUCTION Schizophrenia is a common and complex psychiatric disorder, with proven genetic causes. Research to unravel the genetic basis of schizophrenia has revealed several molecules, including those involved in dopamine and serotonin neurotransmitter systems for the past few decades. Serotonin (5-hydroxytryptamine (5-HT)) hypothesis of schizophrenia has been reanalyzed with the effectiveness of clozapine, the best known atypical antipsychotic drug, 1 as an antagonist for several 5-HT receptors. 2,3 Moreover, 5-HT has been shown to regulate the development of the central nervous system. As the 5-HT transporter (5-HTT) regulates the 5-HT system, 4 alterations in the function of this protein could be involved in the development of schizophrenia. 5 The serotonin transporter (SLC6A4) gene spanning 37.8 kb is located on chromosome 17q11.2, 6,7 and has 14 exons encoding a protein of 630 amino acids. 8 SLC6A4 has received attention as a candidate in schizophrenia and mood disorders, owing to its influence on mood, emotion, cognition and also because 5-HTT is the principal site of action for some antidepressants, particularly for the selective

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The serotonin transporter intronic VNTR enhancer correlated with a predisposition to affective disorders has distinct regulatory elements within the domain based on the primary DNA sequence of the repeat unit

Cited by 113 publications

References 18 publications

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

YB-1 and CTCF Differentially Regulate the 5-HTT Polymorphic Intron 2 Enhancer Which Predisposes to a Variety of Neurological Disorders

Evidence of association of serotonin transporter gene polymorphisms with schizophrenia in a South Indian population

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