Variation of variable number of tandem repeat sequences in the 3′-untranslated region of primate dopamine transporter genes that affects reporter gene expression

Inoue‐Murayama, Miho; Adachi, Shunsuke; Mishima, Nozomu; Mitani, Hiroaki; Takenaka, Osamu; Terao, Keiji; Hayasaka, Ichirô; S, Itó; Murayama, Yuichi

doi:10.1016/s0304-3940(02)01125-4

Cited by 63 publications

(41 citation statements)

References 13 publications

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“…Mutations of SLC6A3 have been associated with striatal DAT activity in animal models [Inoue-Murayama et al, 2002;Miller and Madras, 2002;Mill et al, 2005] and eliminating or reducing dopamine transporter function leads to decreased dopaminergic tone, hyperactivity and deficits in inhibitory behavior in mice [Gainetdinov et al, 1999;Zhuang et al, 2001]. The general agreement between our findings and those published in the adult literature suggests that the 3 0 region of SLC6A3 may be a susceptibility locus for bipolar disorder across the life-cycle.…”

Section: Discussionsupporting

confidence: 85%

Family based association study of pediatric bipolar disorder and the dopamine transporter gene (SLC6A3)

Mick

Kim

Biederman

et al. 2008

American J of Med Genetics Pt B

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The dopamine transporter gene (SLC6A3) is a compelling candidate for pediatric bipolar disorder because (a) it has been associated with ADHD, (b) bipolar comorbidity with ADHD has been hypothesized to be an etiologically distinct familial subtype (c) blockade of the dopamine transporter with psychostimulants can induce mania in susceptible individuals and (d) previous studies have implicated the gene in bipolar disorder in adults. We conducted a family-based association study of SLC6A3 in 170 affected offspring trios defined by a child (12.9 +/- 5.3 years of age)with DSM-IV Bipolar-I disorder. Twenty-eight tag SNPs were chosen from the CEU (European) population of the International HapMap project (www.hapmap.org). Results indicated nominally positive association for 4 SNPs (rs40184, rs11133767, rs3776512, and rs464049), but only rs40184 survived correction for multiple statistical comparisons (P = 0.038). This is the first examination of the association with SLC6A3 and bipolar disorder in children and, like previous findings in adults with bipolar disorder, we found evidence of association with SNPs in the 3' region of the gene. These data provide suggestive evidence supporting a role for SLC6A3 in the etiology of pediatric bipolar disorder.

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Section: Discussionsupporting

confidence: 85%

Family based association study of pediatric bipolar disorder and the dopamine transporter gene (SLC6A3)

Mick

Kim

Biederman

et al. 2008

American J of Med Genetics Pt B

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“…Unfortunately, however, much of the data concerning relationships between DAT expression and 3 haplotypes marked by the exon 15 VNTR is inconsistent. There are reports that find both reduced and enhanced expression driven by human or rhesus DAT 3 untranslated regions with shorter vs. longer VNTRs (Sacchetti et al, 1999;Michelhaugh et al, 2001;Inoue-Murayama et al, 2002;Miller and Madras, Note. "TA" includes haplotypes termed B, E, I and J in Fig.…”

Section: Discussionmentioning

confidence: 99%

Common Human 5′ Dopamine Transporter (SLC6A3) Haplotypes Yield Varying Expression Levels In Vivo

et al. 2006

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1. Individuals display significant differences in their levels of expression of the dopamine transporter (DAT; SLC6A3). These differences in DAT are strong candidates to contribute to individual differences in motor, mnemonic and reward functions. To identify "cis"-acting genetic mechanisms for these individual differences, we have sought variants in 5' aspects of the human DAT gene and identified the haplotypes that these variants define. 2. We report (i) significant relationships between 5' DAT haplotypes and human individual differences in ventral striatal DAT expression assessed in vivo using [(11)C] cocaine PET and (ii) apparent confirmation of these results in studies of DAT expression in postmortem striatum using [(3)H] carboxyflurotropane binding. 3. These observations support the idea that cis-acting variation in 5' aspects of the human DAT/SLC6A3 locus contributes to individual differences in levels of DAT expression in vivo. 5' DAT variation is thus a good candidate to contribute to individual differences in a number of human phenotypes.

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“…However, 2.9% of participants (n = 8) had larger (11) and smaller (6, 7, 8) repeats. DAT 11-repeat alleles behave more similarly to 10-repeat alleles [54], and another study found that both 7- and 9-repeat alleles resulted in less DAT activity than the 10-repeat allele [55]. Therefore, larger repeats were coded as 0 and smaller repeats were coded as 1.…”

Section: Methodsmentioning

confidence: 99%

Dopamine Genetic Risk Score Predicts Depressive Symptoms in Healthy Adults and Adults with Depression

et al. 2014

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BackgroundDepression is a common source of human disability for which etiologic insights remain limited. Although abnormalities of monoamine neurotransmission, including dopamine, are theorized to contribute to the pathophysiology of depression, evidence linking dopamine-related genes to depression has been mixed. The current study sought to address this knowledge-gap by examining whether the combined effect of dopamine polymorphisms was associated with depressive symptomatology in both healthy individuals and individuals with depression.MethodsData were drawn from three independent samples: (1) a discovery sample of healthy adult participants (n = 273); (2) a replication sample of adults with depression (n = 1,267); and (3) a replication sample of healthy adult participants (n = 382). A genetic risk score was created by combining functional polymorphisms from five genes involved in synaptic dopamine availability (COMT and DAT) and dopamine receptor binding (DRD1, DRD2, DRD3).ResultsIn the discovery sample, the genetic risk score was associated with depressive symptomatology (β = −0.80, p = 0.003), with lower dopamine genetic risk scores (indicating lower dopaminergic neurotransmission) predicting higher levels of depression. This result was replicated with a similar genetic risk score based on imputed genetic data from adults with depression (β = −0.51, p = 0.04). Results were of similar magnitude and in the expected direction in a cohort of healthy adult participants (β = −0.86, p = 0.15).ConclusionsSequence variation in multiple genes regulating dopamine neurotransmission may influence depressive symptoms, in a manner that appears to be additive. Further studies are required to confirm the role of genetic variation in dopamine metabolism and depression.

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Variation of variable number of tandem repeat sequences in the 3′-untranslated region of primate dopamine transporter genes that affects reporter gene expression

Cited by 63 publications

References 13 publications

Family based association study of pediatric bipolar disorder and the dopamine transporter gene (SLC6A3)

Family based association study of pediatric bipolar disorder and the dopamine transporter gene (SLC6A3)

Common Human 5′ Dopamine Transporter (SLC6A3) Haplotypes Yield Varying Expression Levels In Vivo

Dopamine Genetic Risk Score Predicts Depressive Symptoms in Healthy Adults and Adults with Depression

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